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  • 1995-1999  (55)
  • 1985-1989  (774)
  • 1998  (55)
  • 1988  (453)
  • 1985  (321)
  • Computational Chemistry and Molecular Modeling  (558)
  • Atomic, Molecular and Optical Physics  (360)
  • pharmacokinetics
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  • 1995-1999  (55)
  • 1985-1989  (774)
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  • 1
    Electronic Resource
    Electronic Resource
    High-dose topotecan with granulocyte-colony stimulating factor in fluoropyrimidine-refractory colorectal cancer: A phase II and pharmacodynamic study (1998)
    Springer
    Annals of oncology 9 (1998), S. 173-180 
    Details
    ISSN: 1569-8041
    Keywords: colorectal cancer ; granulocyte-colony stimulating factor ; pharmacokinetics ; phase II ; topotecan
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: The premise for the study was that topotecan (TPT) resistance in preclinical studies is associated with low level expression of the p-glycoprotein (Pgp) multi-drug transporter conferred by the multi-drug resistant (MDR) phenotype, which might be overcome in clinical practice by administering moderately (2.3-fold) higher doses of TPT that have been shown to be feasible with granulocyte colony-stimulating factor (G-CSF) support. This phase II study evaluated the anti-tumor activity of TPT administered at its highest possible solid tumor dose with G-CSF in patients with fluoropyrimdine-refractory advanced colorectal carcinoma. The study also sought to identify pharmacodynamic (PD) determinants of both activity and toxicity. Patients and methods: TPT was administered as a 30-minute infusion daily for five days every three weeks at a dose of 3.5 mg/m2/day to patients with advanced colorectal carcinoma who developed progressive disease either during treatment with fluoropyrimidine-based chemotherapy for advanced disease or within six months after receiving fluoropyrimdine-based adjuvant chemotherapy. This dose of TPT was previously determined to be the maximal tolerated dose (MTD) with G-CSF support in a phase I study involving solid tumor patients with similar risk factors for myelosuppression. Plasma sampling was performed during course 1 to characterize the pharmacokinetic (PK) and PD behavior of TPT. Results: Seventeen patients who received 89 courses of TPT and G-CSF were evaluable for toxicity; 16 patients were evaluable for anti-tumor response. Toxicity, particularly myelosuppression, was substantial. At the 3.5 mg/m2/day dose level, absolute neutrophil counts (ANC) were less than 500/µl for longer than five days in 17% of courses involving seven of 17 (41%) patients. Severe neutropenia associated with fever occurred in 12.3% of courses; and platelet counts below 25,000/µl were noted in 26.9% of courses. These toxicities resulted in dose reductions in seven of 17 (41%) patients. Nevertheless, 90% of the planned total dose of TPT was administered. No major responses were observed, though minor activity was noted in several patients. Both the median time to progression and the median survival time were short – 2.5 and four months, respectively. Although interindividual variability in the disposition of total TPT was observed, the lack of objective responses precluded PD assessments related to disease activity. Total TPT exposure was significantly higher than drug exposure achieved in similar patients at an identical dose in a previous phase I study of TPT and G-CSF, which may explain why more severe myelosuppressive effects occurred in the present study. There were no PD relationships evident between relevant PK parameters and the percent decrements in platelets and ANCs during course 1, although patients with severe toxic effects (ANC below 500/µl for more than five days and/or platelets 〈25,000/µl) had higher drug exposure than patients with less severe toxicity (P 〈 0.018 and P = 0.09, respectively). Conclusions: Based on these results, the true response rate of TPT at its solid tumor MTD with G-CSF support is unlikely to approach 20%. Although a response rate of less than 20% might be viewed as significant in this disease setting and might be confirmed with sufficient statistical certainty by treating additional patients, the substantial toxicity, inconvenience, and cost associated with this high dose TPT/G-CSF regimen does not warrant the acceptance of a lower level of anti-tumor activity as a criterion for further development.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008266630701
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  • 2
    Electronic Resource
    Electronic Resource
    UGT1A1 genotypes and glucuronidation of SN-38, the active metabolite of irinotecan (1998)
    Springer
    Annals of oncology 9 (1998), S. 845-847 
    Details
    ISSN: 1569-8041
    Keywords: genetic polymorphism ; glucuronidation ; irinotecan ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: Irinotecan (CPT-11) is metabolized by esterase to form a SN-38, which is further conjugated by UGT1A1. Genetic polymorphism has been shown in a promoter region of UGT1A1 and is related to its activity. We investigated whether there might be an inter-individual difference in pharmacokinetics of SN-38 and its glucuronide, depending on the genotypes of UGT1A1. Patients and methods: Nine male patients with lung cancer were treated with irinotecan (50 mg/m2) and carboplatin. Pharmacokinetic parameters were calculated with full sampling plasma data. Genotypes were determined by analyzing the sequence of TATA box of UGT1A1 of genomic DNA from the patients. Results: The genotyping analysis revealed one heterozygote (6/7) and one homozygote (7/7) for (TA)7TAA allele (UGT1A1*28). The remaining seven patients were homozygote for (TA)6TAA allele (6/6, wild type). The metabolic ratios (SN-38/SN-38 glucuronide) in the patient with 7/7 genotype were uncharacteristically higher than those in the patients with other genotypes (6/6 and 6/7). Biliary index was 6980 versus 2180 ± 1110 (range 840–3730) in patients with 7/7 versus 6/6 genotypes, respectively. Conclusion: These results support the idea that the patient with 7/7 genotype has an impaired capacity for glucuronidation of SN-38.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008438109725
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  • 3
    Electronic Resource
    Electronic Resource
    A phase I and pharmacologic study of DMP 840 administered by 24-hour infusion (1998)
    Springer
    Annals of oncology 9 (1998), S. 101-104 
    Details
    ISSN: 1569-8041
    Keywords: DMP 840 ; pharmacodynamics ; pharmacokinetics ; phase I
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: DMP 840, a novel bisnaphthalimide, has demonstrated promising schedule dependent anti-tumor activity in vitro and in vivo against several tumor cell lines. A phase I study was conducted to evaluate the effect of a 24-hour infusion schedule repeated every three weeks, on the therapeutic efficacy of DMP 840. Patients and methods: Fourteen patients with refractory solid tumor malignancies were treated with DMP 840 at doses of 20, 40, 50 and 60 mg/m2. Results: A combination of neutropenia, thrombocytopenia and stomatitis were dose-limiting at doses of 50 and 60 mg/m2 in both minimally- and extensively-pretreated patients. In contrast, all courses at lower dose levels were well tolerated. Pharmacokinetic analysis demonstrated that DMP 840 had a prolonged terminal half life (median 39 hours; range 25–86) and that dose-limiting events were significantly related to several indices of systemic DMP 840 exposure (P 〈 0.01, Wilcoxon Rank Sum test). Conclusion: The recommended dose of DMP 840 for further disease oriented evaluations is 40 mg/m2 administered over 24 hours every three weeks. The infusion duration evaluated in this study did not result in a substantial increase in the tolerable dose compared to shorter, less cumbersome schedules.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008260515869
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  • 4
    Electronic Resource
    Electronic Resource
    Feasibility and pharmacokinetic study of a chimeric anti-CD20 monoclonal antibody (IDEC-C2B8, rituximab) in relapsed B-cell lymphoma (1998)
    Springer
    Annals of oncology 9 (1998), S. 527-534 
    Details
    ISSN: 1569-8041
    Keywords: CD20 ; chimeric IDEC-C2B8 ; lymphoma ; monoclonal antibody ; pharmacokinetics ; feasibility study
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: In clinical trials in the USA, IDEC-C2B8 (a mouse-humanchimeric anti-CD20 monoclonal antibody) has demonstrated high response rateswith only mild toxic effects in relapsed B-cell lymphoma at a dose of fourweekly 375 mg/m2 infusions. The aim of the present trial wasto determine whether or not this dose is practically applicable to Japanesepatients with relapsed B-cell lymphoma with respect to safety,pharmacokinetics and efficacy. Patients and methods: Patients with relapsed CD20+ B-cell lymphomareceived intravenous infusions of IDEC-C2B8 once a week for four weeks. Atotal of 12 patients (four at 250 mg/m2 and eight at 375mg/m2) were enrolled. Results: All 11 eligible patients treated with either dose leveltolerated IDEC-C2B8 well. Commonly observed adverse drug reactions weregrades 1 or 2 non-hematologic toxicities during the infusion, consistingmostly of flu-like symptoms and skin reactions. All of the observedhematologic toxicities were of grade 3 or less, and transient. A rapid andsustained B-cell decrease in peripheral blood was observed, but noinfectious episodes were encountered. Human anti-mouse and anti-chimericantibodies were not detected. Of the 11 eligible patients (eight withfollicular, two with diffuse large-cell and one with mantle cell lymphoma),two showed a complete response and five showed a partial response, and allof the seven responders had lymphoma with follicular histology. Apharmacokinetic analysis showed that the elimination half-life (T1/2) ofIDEC-C2B8 was 445 ± 361 hours, and that the serum antibody levelsincreased in parallel with the course of infusions, and in most patients wasstill measurable at three months. Conclusions: The dose of four weekly 375 mg/m2 infusionsof IDEC-C2B8 is safe and effective in Japanese patients with relapsed B-celllymphoma. Further studies evaluating IDEC-C2B8 are warranted.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008265313133
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  • 5
    Electronic Resource
    Electronic Resource
    Basal activity profiles of NPH and [Nɛ-palmitoyl Lys (B29)] human insulins in subjects with IDDM (1998)
    Springer
    Diabetologia 41 (1998), S. 116-120 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Insulin ; pharmacokinetics ; acylated insulin ; NPH ; insulin therapy ; glucose turnover
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary [Ne-palmitoyl Lys (B29)] human insulin is a fatty acid-acylated derivative of insulin with extended action compared to unmodified insulin when infused intravenously (i. v.) secondary to its binding to circulating albumin. The duration and activity profile of the acylated (A) and NPH (B) insulins were assessed following subcutaneous (s. c.) doses of (A) 6 nmol/kg and (B) 1.2 nmol/kg (equivalent to 0.2 U/kg) in 9 subjects with IDDM. After overnight i.v infusion of regular human insulin, morning glucose was (A) 6.9 ± 0.1 and (B) 6.8 ± 0.1 mmol/l. After the s. c. injection, i. v. human insulin or glucose was infused to maintain near-basal glycaemia and tracer glucose to assess hepatic glucose production (HGP). An activity profile was deduced for each study by expressing the glucose infusion rate at each time point, as a fraction (%) of the basal (measured) HGP, and the i. v. insulin infusion rate as a fraction (%) of the basal requirement. The two fractions are combined by adding the fractional glucose infusion rate and subtracting the fractional insulin infusion rate. Infusion rates of i. v. insulin in the morning were (A) 0.96 ± 0.096 and (B) 1.22 ± 0.09 pmol · kg–1· min–1. After insulin injection, i.v insulin requirements decreased and were below 10 % of basal between 100 and 150 min. A constant activity profile of 0 % represents a perfect substitution of the basal i. v. insulin infusion by the s. c. dose. The actual profile is defined by deviations from this (above) and was –17 ± 11, 7 ± 10, –9 ± 6 and –18 ± 18 % for [Ne-palmitoyl Lys (B29)] human insulin and 17 ± 12, 5 ± 6, –9 ± 15, 22 ± 18 % for NPH insulin at 3, 6, 9 and 12 h after s. c. injection. HGP was similar for the two insulins, demonstrating similar metabolic actions and profiles both peripherally and at the liver. [Diabetologia (1998) 41: 116–120]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250050876
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  • 6
    Electronic Resource
    Electronic Resource
    Impact of early cyclosporin average blood concentration on early kidney transplant failure (1998)
    Springer
    Transplant international 11 (1998), S. 46-52 
    Details
    ISSN: 1432-2277
    Keywords: Key words Cyclosporin ; pharmacokinetics ; kidney transplantation ; Kidney transplantation ; cyclosporin ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This retrospective study served to examine the correlation between the degree of cyclosporin (CyA) exposure, as estimated by a single pharmacokinetic (PK) profile performed at 1 week post-transplant, and the outcome of 290 consecutive renal transplants performed over a 6-year period. For this retrospective analysis patients were stratified into four historical groups based on 12- versus 24-h PK studies and on the use of radioimmunoassay versus fluorescence polarization immunoassay methods for estimates of CyA concentrations. Four PK measures – trough concentration (C0), average concentration values (Cav; i. e., the dosing interval-corrected area under the concentration-time curve), maximum concentration (Cmax), and time to maximum concentration (tmax) – were examined as predictors of patient, graft, and rejection-free survival rates for each of the four groups individually and for all groups combined. Patients with an initial Cav≥ 550 ng/ml had higher 1-year (88 %) and 6-year (66 %) graft survival rates than patients with Cav 〈 550 ng/ml, who had 1- and 6-year graft survival rates of 80 % and 59 %, respectively (P = NS). Statistically significant differences were observed in graft survival rates between patients with Cav 〈 550 versus Cav≥ 550 ng/ml at 30 (88 % vs 96 %; P 〈 0.02), 60 (85 % vs 94 %; P 〈 0.007), 90 (85 % vs 94 %; P 〈 0.02), and 180 (83 % vs 92 %; P 〈 0.05) days. Moreover, patients with Cav 〈 550 ng/ml displayed more severe rejection episodes, as judged by Banff classification, than patients who displayed Cav≥ 550 ng/ml (grades II and III; 71 % vs 50 %; P = 0.036). In contrast, the C0, Cmax, and tmax values did not correlate with patient, graft, or rejection-free survival rates. The pharmacokinetic parameter of Cav correlated strongly with early graft survival and may, therefore, be a useful predictor of those renal transplant patients who may require more intensive post-transplant monitoring of CyA concentrations by serial PK studies to improve graft survival.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001470050101
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  • 7
    Electronic Resource
    Electronic Resource
    Pharmacokinetic and phase I studies of brequinar (DUP 785; NSC 368390) in combination with cisplatin in patients with advanced malignancies (1998)
    Springer
    Investigational new drugs 16 (1998), S. 19-27 
    Details
    ISSN: 1573-0646
    Keywords: phase I ; brequinar ; DUP 785 ; cisplatin ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Brequinar (DUP 785; NSC 368390) is a quinoline carboxylic acid derivative that inhibits pyrimidine synthesis at the level of dihydro-orotate dehydrogenase and revealed synergy with cisplatin in preclinical models. In this study investigating the pharmacokinetic and toxicity of brequinar in combination with cisplatin, patients were initially treated with weekly brequinar, in combination with an every-three-week administration of cisplatin. Due to toxicity, the schedule was modified to a 28-day cycle with brequinar given on days 1, 8, 15, and cisplatin on day 1. A total of 24 patients (16 male, 8 female; median age 57; median performance status 1) received 69 courses of therapy. Six dose levels were explored, with cisplatin/ brequinar doses, respectively, of 50/500, 50/650, 50/860, 60/860, 75/650, and 75/860 mg/m2. The serum concentration versus time curves for brequinar were biphasic. A comparison of the pharmacokinetic results after the first and third doses of brequinar indicate that the presence of 50, 60, and 75 mg/m2cisplatin did not change the protein binding and the pharmacokinetics of brequinar in any of the three brequinar-dose groups. Total cisplatin plasma pharmacokinetic followed a triphasic-shape curve and unbound cisplatin decayed at a very rapid rate. Since pharmacokinetic parameters for total cisplatin in this study were similar to those reported in the literature, the presence of brequinar is unlikely to alter the pharmacokinetics of cisplatin. Main dose-limiting toxicities included myelosuppression (including neutropenia and thrombocytopenia) and mucositis. Cisplatin/brequinar doses of 50/500, 50/650, 50/860, 60/860, 75/650, and 75/860 mg/m2, were associated with dose limiting toxicity in 0/3, 1/3, 1/3, 1/3, 2/4, 2/5, and 4/6 patients, respectively. This study shows that co-administration of brequinar and cisplatin does not affect the pharmacokinetic properties of either drug and that the MTDs of cisplatin/brequinar combinations are 60/860 mg/m2 or 75/650 mg/m2. From this study, we conclude that full dose of 75 mg/m2 cisplatin (day 1) can be administered with 650 mg/m2 brequinar (days 1, 8 and 15) without significant modifications of individual drug pharmacokinetic parameters.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016066529642
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  • 8
    Electronic Resource
    Electronic Resource
    Phase I clinical and pharmacokinetic trial of the podophyllotoxin derivative NK611 administered as intravenous short infusion (1998)
    Springer
    Investigational new drugs 16 (1998), S. 319-324 
    Details
    ISSN: 1573-0646
    Keywords: NK611 ; dimethylaminoetoposide ; Phase I ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Background: NK611 is a novel podophyllotoxin derivative. Compared with etoposide, NK611 carries a dimethyl-amino group at the D-glucose moiety. The antitumor activity of NK611 showed to be equal or superior to etoposide in a variety of in vitro and in vivo tumor models. The aim of our present study was to determine the maximum tolerated dose and the dose-limiting toxicities of NK611 administered as intravenous infusion over 30 min every 28 days. Patients and methods: 45 patients (7 female, 38 male; median age 54 [range 37–73]) were enrolled. In a first stage, NK611 was administered without hematopoietic growth factor support; in a second stage, G-CSF was used for further dose escalation. Toxicities were assessed using WHO-criteria. Results: Initially, the dose was escalated from 60 mg/m2 to 120 mg/m2. In a second patient cohort, doses were further escalated with G-CSF support with doses ranging from 140 mg/m2 to 250 mg/m2. Dose-limiting toxicities were granulocytopenia and thrombocytopenia. Non-hematologic toxicities consisted of alopecia, mild nausea, and infection. Four partial responses were observed: two at 200 mg/m2 (pleural mesothelioma, response duration 7 months, and non-small cell lung cancer, response duration 13 months), and two at 250 mg/m2 (hepatocellular carcinoma, response duration 7 months, and non-small cell lung cancer, response duration 2 months). Pharmacokinetic analyses were performed in all patients. Using an open 3-compartment model, the terminal half-life (t1/2γ) was 14.7 ± 3.7 h. The AUC at 250 mg/m2 was determined to be 330 ± 147 μg/mlh, the plasma clearance of NK611 was 16.2 ± 8.2 ml/min · m2 and the Vss was 16.8 ± 3.3 l/m2. Protein binding of NK611 was 98.7%. Conclusion: the recommended dose for clinical Phase II studies is 120 mg/m2 without G-CSF support and 200 mg/m2 with G-CSF support.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006293830585
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  • 9
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and Relative Bioavailability of Carboxyamido-Triazole with Respect to Food and Time of Administration: Use of a Single Model for Simultaneous Determination of Changing Parameters (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 673-687 
    Details
    ISSN: 1573-8744
    Keywords: carboxyamido-triazole ; bioavailability ; chronopharmacology ; pharmacokinetics ; food
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Carboxyamido-triazole (CAI) is an anti-invasive, antimetastatic, antiangiogenic agent in clinical development for cancer treatment. It has been postulated that food might enhance the oral absorption of micronized CAI based on an apparent discrepancy in steady state maximum concentrations when taken without regard to meals vs. fasting. The purpose of this study was to determine if a standardized meal affects the absorption and pharmacokinetics of this agent. Twelve patients with refractory cancers and good end organ function were randomized to receive two doses of CAI (250 mg/m 2 ) with and without a standardized high fat meal. One cohort of 6 patients received these doses at 9 AM, and the remaining 6 patients received CAI at 9 PM. Blood was obtained prior to each dose, and serially thereafter. A series of pharmacokinetic (PK) models were fit to the concentration–time data. PK parameters were ultimately calculated using a model which allows simultaneous estimation of parameters from both test doses using nonlinear least squares analysis with ADAPT II. This model estimates independent absorption rate constants and relative fraction absorbed for each condition. AUC 0–t was determined using the trapezoidal method, extrapolated to infinity, and used to calculate the relative bioavailability. No significant differences in PK parameters were noted between the morning and evening cohorts. However, the relative bioavailability, as measured by AUC 0–∞, of CAI was significantly increased when administered with a high fat meal compared to fasting (138.9 vs. 52.2 μg * hr/ml; p=0.0005). The magnitude of the increase in relative bioavailability of CAI taken with food could have profound implications for patients who may inadvertently take this medication shortly after eating.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1020750923542
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  • 10
    Electronic Resource
    Electronic Resource
    A preliminary study of the pharmacokinetics of fenoprofen enantiomers following intravenous administration of the racemate to cats (1998)
    Springer
    Veterinary research communications 22 (1998), S. 203-208 
    Details
    ISSN: 1573-7446
    Keywords: anti-inflammatory ; cat ; enantiomer ; fenoprofen ; NSAID ; pharmacokinetics ; racemic ; stereoselectivity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006077406388
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  • 11
    Electronic Resource
    Electronic Resource
    Some Pharmacokinetic Parameters and Dosage Regimens for a Long-Acting Formulation of Oxytetracycline in 6- to 8-Month-Old Male Calves (1998)
    Springer
    Veterinary research communications 22 (1998), S. 533-544 
    Details
    ISSN: 1573-7446
    Keywords: calves ; dosage regimen ; oxytetracycline ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A two-way crossover study was conducted in crossbred male calves (6–8 months old) to determine the bioavailability, pharmacokinetics and dosage regimens for a long-acting formulation of oxytetracycline (OTC-LA). The half-lives of oxytetracycline after intravenous and intramuscular administration were 7.8 h and 24 h, respectively. The volume of distribution and total body clearance values of the drug were 0.86±0.07 L and 76.1±3.3 (ml/h)/kg, respectively. The maximum concentration of the drug in the serum (4.7–7.4 μg/ml) was achieved 8–10 h after intramuscular administration. The minimum therapeutic serum concentration of drug of ≥0.5 μg/ml was maintained between 15 min and 84 h after intramuscular administration. The intramuscular bioavailability of the drug was 89.1±4.2%. The dosage regimens to maintain the minimum therapeutic serum concentrations of OTC following intramuscular administration of OTC-LA were computed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006193703979
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  • 12
    Electronic Resource
    Electronic Resource
    The Pharmacokinetics and Efficacy of Long-Term Low-Level and Split-Dose Administration of Albendazole Through In-Feed Formulations against Ovine and Caprine Parasitic Gastroenteritis (1998)
    Springer
    Veterinary research communications 22 (1998), S. 467-477 
    Details
    ISSN: 1573-7446
    Keywords: albendazole ; anthelmintic ; goat ; in-feed ; metabolite ; pharmacokinetics ; sheep
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Two trials were conducted against natural and experimentally induced parasitic gastroenteritis in sheep and goats using an in-feed formulation of albendazole to evaluate its therapeutic and prophylactic efficacy. In the first trial, albendazole was incorporated in feed pellets to deliver an average daily dose of 0.7 mg/kg body weight in order to evaluate its prophylactic efficacy. In the second trial, feed pellets were offered to deliver an average total dose of 8.0 mg/kg body weight in two equal split doses in order to evaluate its curative efficacy. Sustained plasma concentrations of the active compound, albendazole sulphoxide, and its metabolite albendazole sulphone, sufficient to prevent establishment of infection, were achieved when the animals were allowed to feed on medicated pellets for 10 consecutive days. The bioavailability of the metabolites of albendazole following the administration of a therapeutic dose in two split doses of the in-feed formulation was sufficient to remove established adult nematodes. The concentrate feed pellets could be used for self-medicating small ruminants for therapeutic use as well as for prophylaxis based on their strategic use appropriate to the epidemiology of the parasitic disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006127132161
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  • 13
    Electronic Resource
    Electronic Resource
    Plasma, Urinary and Biliary Residues in Cattle Following Intramuscular Injection of Nortestosterone Laurate (1998)
    Springer
    Veterinary research communications 22 (1998), S. 479-491 
    Details
    ISSN: 1573-7446
    Keywords: cattle ; nortestosterone ; pharmacokinetics ; residues
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The synthetic androgen 19-nortestosterone (β-NT) has been used illegally as a growth promoter in cattle production in the European Union. Elimination of β-NT and its metabolites in plasma, urine and bile was studied in three cattle with cannulated gallbladders following intramuscular injection at a single site of 500 mg of the laurate ester (NTL) containing 300.5 mg β-NT. Using enzyme immunoassay quantification, plasma Cmax of free β-NT was 0.5±0.15 μg/L (mean±SEM). Concentrations of free β-NT in plasma were consistently greater than the assay limit of quantification (0.12 μg/L) for 32.7±13.42 days. Mean residence time for free β-NT in plasma was 68.5±20.75 days. Following sample preparation by immunoaffinity chromatography, high-resolution GC-MS was used to quantify β-NT and α-NT in urine and bile. β-NT was detected irregularly in urine from two of the three animals post injection. The principal metabolite present in the urine, α-NT, was detected for 160.3±22.67 days post injection. Cmax for α-NT in urine was 13.7±5.14 μg/L. Mean urinary AUC0–183 days for α-NT was 845.7±400.90 (μg h)/L. In bile, α-NT was the only metabolite detected for 174.3±8.67 days post treatment. Cmax for α-NT in bile was 40.8±12.70 μg/L and mean biliary AUC0–183 days for α-NT was 1982.6±373.81 (μg h)/L. Concentrations of α-NT in bile samples were greater than those in urine samples taken at the same time. The mean ratio of biliary:urinary AUC0–183 days was 3.0±0.72. It is concluded that bile is a superior fluid for detection of α-NT following injection of NTL, owing to the longer period during which residues may be detected after administration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006179116231
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  • 14
    Electronic Resource
    Electronic Resource
    Comparative Disposition Kinetics of Albendazole in Sheep Following Oral and Intraruminal Administration (1998)
    Springer
    Veterinary research communications 22 (1998), S. 545-551 
    Details
    ISSN: 1573-7446
    Keywords: albendazole ; metabolites ; pharmacokinetics ; route of administration ; sheep
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The pharmacokinetics of albendazole was studied in sheep following single oral and intraruminal administration at nematocidal dose rates. The disposition curves of its metabolites indicated increased uptake of the drug in sheep following intraruminal as compared to oral dosing (p〈0.05). The increased bioavailability of benzimidazole anthelmintics given by the intraruminal route could be exploited for optimizing the use of anthelmintic for sustained parasite control in small ruminants.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006145820818
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  • 15
    Electronic Resource
    Electronic Resource
    Lumping of Whole-Body Physiologically Based Pharmacokinetic Models (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 21-46 
    Details
    ISSN: 1573-8744
    Keywords: pharmacokinetics ; whole body physiologically based model ; lumping ; system theory ; barbiturates
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Lumping is a common pragmatic approach aimed at the reduction of whole-body physiologically based pharmacokinetic (PBPK) model dimensionality and complexity. Incorrect lumping is equivalent to model misspecification with all the negative consequences to the subsequent model implementation. Proper lumping should guarantee that no useful information about the kinetics of the underlying processes is lost. To enforce this guarantee, formal standard lumping procedures and techniques need to be defined and implemented. This study examines the lumping process from a system theory point of view, which provides a formal basis for the derivation of principles and standard procedures of lumping. The lumping principle in PBPK modeling is defined as follows: Only tissues with identical model specification, and occupying identical positions in the system structure should be lumped together at each lumping iteration. In order to lump together parallel tissues, they should have similar or close time constants. In order to lump together serial tissues, they should equilibrate very rapidly with one another. The lumping procedure should include the following stages: (i) tissue specification conversion (when tissues with different model specifications are to be lumped together); (ii) classification of the tissues into classes with significantly different kinetics, according to the basic principle of lumping above; (iii) calculation of the parameters of the lumped compartments; (iv) simulation of the lumped system; (v) lumping of the experimental data; and (vi) verification of the lumped model. The use of the lumping principles and procedures to be adopted is illustrated with an example of a commonly implemented whole-body physiologically based pharmacokinetic model structure to characterize the pharmacokinetics of a homologous series of barbiturates in the rat.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1023272707390
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  • 16
    Electronic Resource
    Electronic Resource
    Population Pharmacokinetic Analysis of Mizolastine and Validation from Sparse Data on Patients Using the Nonparametric Maximum Likelihood Method (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 133-161 
    Details
    ISSN: 1573-8744
    Keywords: mizolastine ; pharmacokinetics ; population analysis ; zero-order absorption ; heteroscedastic variance ; NPML ; validation ; predictive distributions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A population analysis of the kinetics of mizolastine was performed from concentrations on 449 allergic patients, using the nonparametric maximum likelihood method (NPML). A two-compartment open model with zero-order absorption was used to describe the kinetics of mizolastine after oral administration. A heteroscedastic variance model was assumed for the error. To explain the kinetic variability, eight covariates were introduced in the analysis: gender, pharmaceutical dosage form, age, body weight, serum creatinine concentration, creatinine renal clearance, plasma levels of hepatic transaminases ASAT and ALAT. Their relationships to the kinetic parameters were studied by means of the estimated distribution of each kinetic parameter conditional on different levels of each covariate. An important interindividual kinetic variability was found for all parameters. Moreover, several kinetic parameters among which the duration of absorption were found to be influenced by pharmaceutical dosage form and gender. Body weight and creatinine renal clearance were found to have a little influence on the oral clearance and the smallest disposition rate constant. This population analysis was validated on a separate group of 247 other patients. For each observed concentration of this sample, a predictive distribution was computed using the individual covariates. Predicted concentrations and standardized prediction errors were deduced. The mean and variance of the standardized prediction errors were, respectively, 0.21 and 2.79. Moreover, in the validation sample, the predicted cumulative distribution function of each observed concentration was computed. Empirical distribution of these values was not significantly different from a uniform distribution, as expected under the assumption that the population model estimated by NPML is adequate.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1020505722924
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  • 17
    Electronic Resource
    Electronic Resource
    Rapid Attainment of Steady State Plasma Drug Concentrations Within Precise Limits (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 319-328 
    Details
    ISSN: 1573-8744
    Keywords: anesthetic techniques ; continuous infusion ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract We describe a method of rapidly obtaining a specified steady state plasma concentration of an intravenous drug within precise limits. The technique requires an initial bolus to raise the plasma concentration to the upper limit followed by a series of constant-rate infusions each of which is associated with a minimum plasma concentration equal to the tower limit. The infusion rate is stepped down when the plasma concentration returns to the upper limit. Computer simulation, based on the method, is used to generate plasma concentration–time curves with fluctuations of up to 10% about selected steady state concentrations of amrinone, esmolol, lidocaine, midazolam, propofol, and theophylline. The utility of this general approach to intravenous dosing and potential limitations of the method are discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1023285426388
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  • 18
    Electronic Resource
    Electronic Resource
    Fourth-Generation Model for Corticosteroid Pharmacodynamics: A Model for Methylprednisolone Effects on Receptor/Gene-Mediated Glucocorticoid Receptor Down-Regulation and Tyrosine Aminotransferase Induction in Rat Liver (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 289-317 
    Details
    ISSN: 1573-8744
    Keywords: methylprednisolone ; pharmacokinetics ; pharmacodynamics ; indirect response models ; glucocorticoid receptor ; tyrosine aminotransferase ; Northern hybridization ; mRNA ; down-regulation ; receptor recycling
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A fourth-generation pharmacokinetic/pharmacodynamic (PK/PD) model for receptor/genemediated effects of corticosteroids was developed. Male adrenalectomized Wistar rats received a 50 mg/kg iv bolus dose of methylprednisolone (MPL). Plasma concentrations of MPL, hepatic glucocorticoid receptor (GR) messenger RNA (mRNA) and GR density, tyrosine aminotransferase (TAT) mRNA, and TAT activity in liver were determined at various time points up to 72 hr after MPL dosing. Down-regulation of GR mRNA and GR density were observed: GR mRNA level declined to 45–50% of the baseline in 8–10 hr, and slowly returned to predose level in about 3 days; GR density fell to 0 soon after dosing and returned to the baseline in two phases. The first phase, occurring in the first 10 hr, entailed recovery from 0 to 30%. The second phase was parallel to the GR mRNA recovery phase. Two indirect response models were applied for GR mRNA dynamics regulated by activated steroid-receptor complex. A full PK/PD model for GR mRNA/GR down-regulation was proposed, including GR recycling theory. TAT mRNA began to increase at about 1.5 hr, reached the maximum at about 5.5 hr, and declined to the baseline at about 14 hr after MPL dosing. TAT induction followed a similar pattern with a delay of about 1–2 hr. A transcription compartment was applied as one of the cascade events leading to TAT mRNA and TAT induction. Pharmacodynamic parameters were obtained by fitting seven differential equations piecewise using the maximum likelihood method in the ADAPT II program. This model can describe GR down-regulation and the precursor/product relationship between TAT mRNA and TAT in receptor/gene-mediated corticosteroid effects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1023233409550
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  • 19
    Electronic Resource
    Electronic Resource
    Optimal Experimental Design for Precise Estimation of the Parameters of the Axial Dispersion Model of Hepatic Elimination (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 595-615 
    Details
    ISSN: 1573-8744
    Keywords: optimal design ; hepatic elimination models ; parameter estimation ; protein binding ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The axial dispersion model of hepatic drug elimination is characterized by two dimensionless parameters, the dispersion number, DN , and the efficiency number, RN , corresponding to the relative dispersion of material on transit through the organ and the relative efficiency of elimination of drug by the organ, respectively. Optimal design theory was applied to the estimation of these two parameters based on changes in availability (F) of drug at steady state for the closed boundary condition model, with particular attention to variations in the fraction of drug unbound in the perfusate (fuB ). Sensitivity analysis indicates that precision in parameter estimation is greatest when F is low and that correlation between RN and DN is high, which is desirable for parameter estimation, when DN lies between 0.1 and 100. Optimal design points were obtained using D-optimization, taking into account the error variance model. If the error variance model is unknown, it is shown that choosing Poisson error model is reasonable. Furthermore, although not optimal, geometric spacing of fuB values is often reasonable and definitively superior to a uniform spacing strategy. In practice, the range of fuB available for selection may be limited by such practical considerations as assay sensitivity and acceptable concentration range of binding protein. Notwithstanding, optimal design theory provides a rational approach to precise parameter estimation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1023229318017
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  • 20
    Electronic Resource
    Electronic Resource
    Single-Dose Pharmacokinetics of Rifapentine in Women (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 75-85 
    Details
    ISSN: 1573-8744
    Keywords: rifapentine ; pharmacokinetics ; gender differences ; female
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Gender can be an important variable in the absorption and disposition of some drugs. In this open-label study, 15 healthy, nonsmoking women received a single 600-mg oral dose of rifapentine. Plasma samples were obtained at frequent intervals for up to 72 hr after the dose to determine the pharmacokinetic (PK) parameters of rifapentine and its active metabolite, 25-desacetyl-rifapentine. Peak plasma rifapentine concentrations (Cmax ) were observed 5.9 hr after ingestion of the single dose. The mean area under the rifapentine plasma concentration–time curve [AUC(0 → ∞ )] was 325 μg · hr ml and the mean elimination half-life (t1/2 ) was 16.3 hr. Plasma concentrations for the 25-desacetyl metabolite peaked at 15.4 hr after the rifapentine dose and declined with a terminal half-life of 17.3 hr. These rifapentine and 25-desacetyl-rifapentine PK data in women were compared to data generated previously in healthy men. Striking similarities in the PK profiles of parent drug and metabolite were found in the two populations. Mean differences in rifapentine CL/F (12%) and t1/2 (2%) were small. The only adverse event reported in the female subjects was discoloration of the urine. Based on these PK and safety data, no dosage adjustments for rifapentine based on gender are recommended.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1023276808298
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  • 21
    Electronic Resource
    Electronic Resource
    Pharmacokinetic and Pharmacodynamic Evaluation for Tissue-Selective Inhibition of Cholesterol Synthesis by Pravastatin (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 329-347 
    Details
    ISSN: 1573-8744
    Keywords: HMG-CoA reductase inhibitors ; pravastatin ; tissue-selectivity ; cholesterol synthesis ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The tissue-selective inhibition of cholesterol synthesis by pravastatin was evaluated pharmacokinetically and pharmacodynamically. Plasma, tissue, urine, and bile concentrations were measured after iv bolus injection of pravastatin to rats at various doses. The total body clearance and steady state volume of distribution decreased with increasing dose. A saturable biliary excretion was also observed. The time course of plasma and liver concentrations was described by a three-compartment model, consisting of a central compartment, a deep compartment with an nonsaturable uptake process, and a shallow compartment with saturable uptake and nonsaturable elimination processes. It suggests that a mechanism for the decrease in the total body clearance and distribution volume might be explained by a saturation of pravastatin uptake into the liver. Plasma concentration data after oral administration was also fitted to the same model by connecting an absorption compartment to the shallow compartment. The inhibitory activity of pravastatin against cholesterol synthesis in liver could be related to the concentration in the shallow compartment via a sigmoidal Emax model and the obtained pharmacodynamic parameters were comparable to those in vitro. Results suggest that the carrier-mediated hepatic uptake of pravastatin is actually responsible for the hepatoselective inhibition of cholesterol synthesis under physiological conditions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1023237510458
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  • 22
    Electronic Resource
    Electronic Resource
    Mathematical Formalism and Characteristics of Four Basic Models of Indirect Pharmacodynamic Responses for Drug Infusions (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 385-408 
    Details
    ISSN: 1573-8744
    Keywords: pharmacodynamics ; pharmacokinetics ; indirect response models ; infusions ; inhibition ; stimulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Indirect response models require differential equations to describe the nonlinear inhibition or stimulation of the production or loss (kout ) of the response variable. Partially integrated solutions for these models developed previously for iv bolus or biphasic pharmacokinetics were extended to consider drug infusions for limited or extended durations. Qualitative examination was made of the role of infusion rate and duration, type and rate of drug disposition, Imax or Smax capacity factors, IC50 or SC50 sensitivity factors, and kout values. Properties of the response curves characterized include curve shapes, maximum or minimum response, onset rate, steady-state, and return to baseline. Some comparisons were made with behavior of iv bolus doses. These relationships provide both a formal and practical basis for better understanding of the time-course of basic indirect response models.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1021060000789
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  • 23
    Electronic Resource
    Electronic Resource
    Integrated Pharmacokinetic–Pharmacodynamic Model for Acetaminophen, Ibuprofen, and Placebo Antipyresis in Children (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 559-579 
    Details
    ISSN: 1573-8744
    Keywords: acetaminophen ; age ; antipyretic ; fever ; ibuprofen ; pediatrics ; pharmacokinetics ; pharmacodynamics ; temperature
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A descriptive profile for antipyretic drug action has been documented for children. However, a linked pharmacokinetic–pharmacodynamic (PK/PD) model is central to the understanding of antipyretic drug action in febrile children. This was examined for previously reported data from 178 febrile children who received a single oral dose of acetaminophen (APAP) (12.5 mg/kg), ibuprofen (IBU) (5 or 10 mg/kg), or placebo. Rectal temperatures and plasma levels (μg/ml) of APAP and IBU were measured for up to 12 hr after drug administration. Nonlinear regression analyses were applied to these measurements and yielded simultaneous solutions of an integrated one-compartment PK, link, and SigmoidEmax effect model in 102/153 febrile children given APAP or IBU. The PK parameters (tlag ,ka , β,T1 / 2β ,AUC0–∞ ,Vd/F,andClp/F) were not different than those reported previously, except the APAPka was significantly lower. The link component yieldedkeo s of 0.58±0.06 (X±SE), 0.70±0.11 and 0.57 ± 0.11 hr -1 for APAP, IBU05, and IBU10, respectively: the SigmoidEmax component yieldedEC50 s (μg/ml) and sigmoidicity (γ) of 4.63±0.39 and 3.98±0.42 for APAP, 11.33±1.35 and 3.97±0.58 for IBU05 and 12.83±1.89 and 4.27±0.63 for IBU10. On visual inspection of the efficacy–time profiles of the febrile children, a number of them had an apparent linear function (slope; Δ°C/hr) and/or a sinusoidal cyclic function “confounding” standard approaches to PD analysis. Thus, the temperature profiles of 91/102 children given APAP or IBU required the addition of a slope (Δ°C/hr) and/or a sinusoidal cyclic function to the SigmoidEmax component to fit the data satisfactorily. All 22 children given a placebo also required a slope and/or a cyclic function in their PD model. The residual Δ°Cs (observed-predicted) of the placebo group were not significantly different from 0. Thus, no placebo antipyretic effect was observed. Dose dependency of IBUAUC0–∞ was confirmed; doubling the dose from 5 to 10 mg/kg increased theAUC0→∞ by only 1.5-fold. The confounding effect of initial temperature (Tempi ) on antipyretic efficacy in all treatment groups except placebo was also confirmed to expose nonlinear pharmacodynamics. A significant (p=0.03) contribution ofTempi (but not age) on the value of the slope function was found. There was no consistent effect of age orTempi , on the cyclic component of the integrated model of antipyresis. In addition, a multiple linear relationship of age andTempi was observed with a large number of the PK, link, and PD variables in those who received IBU. Dose, age, andTempi interacted with β in a significant multiple linear relationship withAUC0–∞ . The effects of IBU dose, age, andTempi are pervasive and cascade down the chain of events leading to the PD response. The etiology of pyresis may create the slope function, the magnitude of which may be partially due to the underlying disease. In some cases, the cyclic function may be explained by temperature regulation. Regardless of their cause, both confound analysis of drug action and make the simple, unmodified SigmoidEMax effect model less than satisfactory for interpretation of antipyretic drug effects. The influence of Tempi on the magnitude of antipyretic drug response is also a finding with major impact on PD investigations of antipyretic medications. In children receiving IBU, dose and age are also confounders, in addition toTempi . A multiplicity of covariables must be taken into account when developing appropriate dosing regimens for these antipyretics in febrile children.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1023225217108
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  • 24
    Electronic Resource
    Electronic Resource
    Dose-Dependence and Repeated-Dose Studies for Receptor/Gene-Mediated Pharmacodynamics of Methylprednisolone on Glucocorticoid Receptor Down-Regulation and Tyrosine Aminotransferase Induction in Rat Liver (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 619-648 
    Details
    ISSN: 1573-8744
    Keywords: methylprednisolone ; pharmacokinetics ; pharmacodynamics ; indirect pharmacodynamic response models ; glucocorticoid receptor ; Northern hybridization ; mRNA ; down-regulation ; tyrosine aminotransferase ; dose dependence ; tolerance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Dose-dependent and repeated-dose effects of methylprednisolone (MPL) on down-regulation of glucocorticoid receptor messenger RNA (GR mRNA) and GR density, as well as tyrosine aminotransferase (TAT) mRNA and TAT induction by receptor/gene-mediated mechanisms in rat liver were examined. A previously developed pharmacokinetic/pharmacodynamic (PK/PD) model was used to design these studies which sought to challenge the model. Three groups of male adrenalectomized Wistar rats received MPL by iv injection: low-dose (10 mg/kg at Time 0), high-dose (50 mg/kg at Time 0), and dual-dose (50 mg/kg at Time 0 and 24 hr). Plasma concentrations of MPL, and hepatic content of free GR, GR mRNA, TAT mRNA, and TAT activity were determined. The P-Pharm program was applied for population analysis of MPL PK revealing low interindividual variation in CL and Vc values (3–14%). Two indirect response models were applied to test two competing hypotheses for GR mRNA dynamics. Indirect Pharmacodynamic Response Model I (Model A) where the complex in the nucleus decreases the transcription rate of GR mRNA better described GR mRNA/GR down-regulation. Levels of TAT mRNA began to increase at 1–2 hr, reached a maximum at 5–6 hr, and declined to the baseline at 12–14 hr after MPL dosing. The induction of TAT activity followed a similar pattern with a delay of about 1–2 hr. The low-dose group had 50–60% of the TAT mRNA and TAT induction compared to the high-dose group. Since the GR density returned to about 70% of the baseline level before the second 50 mg/kg dose at 24 hr, tolerance was found for TAT mRNA/TAT induction where only 50–60% of the initial responses were produced. Our fourth-generation model describes the dose dependence and tolerance effects of TAT mRNA/TAT induction by MPL involving multiple-step signal transduction controlled by the steroid regimen, free GR density, and GR occupancy. This model may provide the foundation for studying other induced proteins or enzymes mediated by the similar receptor/nuclear events.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1020746822634
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  • 25
    Electronic Resource
    Electronic Resource
    Characterization of Pharmacodynamic Recession Slopes for Direct and Indirect Response Models (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 409-436 
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    ISSN: 1573-8744
    Keywords: pharmacodynamic recession slope ; Hill function ; k · m product ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Direct pharmacologic effects are known to recede over time with largely linear slopes (Levy's k · m product, J. Pharm. Sci. 53: 342, 1964) and indirect responses have similar behavior. Pharmacodynamic slope properties were examined mathematically for the Hill function with monoexponential drug disposition and simulations were carried out for other pharmacokinetic functions. Both types of pharmacodynamic profiles exhibit a single terminal inflection point (fp) when drug concentrations exceed the EC50 (that concentration causing one-half maximum effect, Emax ). For direct effects it was found that Cfp (the drug concentration at fp) =EC50 , the determinants of inflection time were identified, and Slopefp = −λzγEmax /4 where λz is the terminal disposition slope and γ is the Hill coefficient. These characteristics were explored for the four basic indirect response models which also exhibit recession profiles with slight sigmoidity and a single terminal inflection point at higher doses. The drug concentration at inflection Cfp is ≤IC50 or SC50 (drug concentrations causing half-maximal inhibition or stimulation), while the inflection response (Rfp ) attains constant values at larger doses. Indirect Response Models I, III, and IV have nearly linear return slopes for a wide range of doses which are governed by the disposition slope λz of the drug, loss constant kout of the response, maximum inhibition (Imax ) or stimulation (Smax ) factors, and a unique fractional constant (0〈G≤1). Model II exhibits more complex behavior with recession slopes which are less likely to be parallel for various doses. Most indirect responses are expected to show nearly linear recession slopes which are parallel for moderate to large doses and mainly governed by an identical combination of pharmacokinetic (λz ), system (kout ), and dynamic capacity factors (Imax or Smax ).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1021012117627
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  • 26
    Electronic Resource
    Electronic Resource
    Effects of Intestinal and Hepatic Metabolism on the Bioavailability of Tacrolimus in Rats (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1609-1613 
    Details
    ISSN: 1573-904X
    Keywords: tacrolimus ; bioavailability ; metabolism ; intestine ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Tacrolimus, an immunosuppressive agent, has poor and variable bioavailability following oral administration in clinical use. We investigated the contribution of intestinal metabolism to the first pass effect of tacrolimus in rats. Methods. Tacrolimus was administered intravenously, intraportally or intraintestinally to rats. Blood samples were collected over a 240-min period, and blood tacrolimus concentrations were measured. The extraction ratios of tacrolimus in the intestine and liver were investigated. In addition, the metabolism of tacrolimus in the everted sacs of the small intestine was examined. Results. The rate of absorption of tacrolimus in the intestine was rapid, and tacrolimus was almost completely absorbed after intestinal administration. The bioavailability of tacrolimus was about 40% and 25% after intraportal and intraintestinal administration, respectively, indicating that tacrolimus is metabolized in both the intestine and the liver. In addition, tacrolimus was significantly metabolized in the everted sacs of the rat intestine. Conclusions. The present study suggested that the metabolism of tacrolimus in the intestine contributes to its extensive and variable first pass metabolism following the oral administration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011967519752
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  • 27
    Electronic Resource
    Electronic Resource
    Human Drug Absorption Kinetics and Comparison to Caco-2 Monolayer Permeabilities (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 47-52 
    Details
    ISSN: 1573-904X
    Keywords: permeability ; oral absorption ; Caco-2 cells ; pharmacokinetics ; human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. This study aims to assess the drug absorption kinetics of three drugs and compare their resulting first-order intestinal permeation rate constants to their Caco-2 monolayer permeabilities. Methods. In vitro dissolution — in vivo absorption analysis was conducted on four formulations of each ranitidine HC1, metoprolol tartrate, and piroxicam to yield apparent and "true” human clinical permeation rate constants. Drug permeability coefficients through Caco-2 monolayers were also determined. Results. In vitro dissolution — in vivo absorption analysis revealed different relative and absolute contributions of dissolution and intestinal permeation to overall drug absorption kinetics for various drug formulations and yielded estimates of each drug's true and apparent human intestinal permeation rate constant [k p = 0.225 hr−1, 0.609 hr−l, and 9.00 hr−1 for ranitidine, metoprolol, and piroxicam, respectively]. A rank order relationship was observed for both the apparent and true permeation rate constant with Caco-2 monolayer permeability. The decrease in the true permeation rate constant relative to the apparent permeation rate constant was most significant (almost three-fold) for the least permeable compound, ranitidine. Conclusions. There were marked differences in the permeation kinetics of ranitidine, metoprolol, and piroxicam. The possibility of an association between absorption kinetics from dosage forms in humans and Caco-2 monolayer permeability may allow for a direct kinetic interpretation of human oral absorption from Caco-2 monolayer permeability values.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011992518592
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  • 28
    Electronic Resource
    Electronic Resource
    Rapid Determination of Oral Pharmacokinetics and Plasma Free Fraction Using Cocktail Approaches: Methods and Application (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 93-97 
    Details
    ISSN: 1573-904X
    Keywords: cocktail dosing ; pharmacokinetics ; plasma free fraction ; ultrafiltration ; HPLC/APCI/MS
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To apply cocktail approaches for protein binding (PB) and pharmacokinetics (PK) within a discovery program as a means of providing timely systemic exposure (AUC and Cmax) data. Methods. For PB data, a procedure of cocktail ultrafiltration, mixed matrix sample preparation and single quadrupole atmospheric pressure ionization LC/MS analysis was used. In vivo PK studies consisted of 4 experimental compounds and a control compound dosed orally at 1 mg/kg (5 mg/kg total dose), with plasma samples obtained at 0.5, 1, 2, 4 and 8 h post dose. For PB and in vivo PK analysis, a control compound was tested within each cocktail to ensure consistent reproducibility. Results. Approximately 2 weeks were spent comparing single and cocktail approaches to determine the feasibility of this method for this project. Comparisons of cocktail data with single compound data revealed no significant differences between the approaches. The oral AUC values ranged from 0.01 to 9.28 μg⋅hr/ml and the Cmax values ranged from 0.04 to 2.17 μg/ml. Free fractions of the 44 compounds studied ranged from 0.006 to 0.271. Using the free fraction values to correct for free AUC and Cmax results in ranges of 0.001 to 0.473 μg⋅hr/ml, and 0.001 to 0.119 μg/ml, respectively. Conclusions. All 44 compounds tested had similar potencies in vivo. Thus, these results suggest that a respective 400 and 100-fold range in AUC and Cmax corrected for free fraction exist in the presence of comparable in vivo activity. The ability to generate this type of data in a timely manner allowed the selection of a candidate with low peripheral exposure relative to the effective dose. The free fraction and PK data on the 44 compounds described was collected within three work days by 2 lab scientists.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011909022226
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  • 29
    Electronic Resource
    Electronic Resource
    Elucidation of Human Amphotericin B Pharmacokinetics: Identification of a New Potential Factor Affecting Interspecies Pharmacokinetic Scaling (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1630-1636 
    Details
    ISSN: 1573-904X
    Keywords: amphotericin B ; pharmacokinetics ; human ; gender-differences ; disposition function differences ; interspecies scaling
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To elucidate the pharmacokinetics of amphotericin B in rats, mice and humans, and to perform interspecies scaling to humans using allometry. Methods. Plasma concentrations following intravenous bolus administration in rats, and mice were determined by HPLC. Human pharmacokinetic parameters elucidated from literature data were validated in a preliminary study involving a patient receiving daily infusion dose for 27 days. A critical literature review was conducted to identify appropriate pharmacokinetic parameter values in other species for interspecies scale-up. Interspecies allometric scale-up was performed across mice, rats, rabbits and dogs and the resulting predictions in humans were compared to observed values. Results. A triexponential decline in rat, mouse and human plasma concentrations were observed. No gender differences in rat pharmacokinetics were observed. In contrast to allometry, mouse CL was smaller (82 vs 116 ml/h/kg) and T0.5 (33 vs 20 h) was longer compared to rat. In the preliminary human study, Cpeak and Cmin values remained relatively constant over the duration of therapy, and a CL, MRT, T0.5, Vss and Vdarea of 26 ml/h/kg, 10 and 23 days, 6.2 and 20 L/kg, respectively, were estimated. The relative contributions of the terminal phase area in rat, mouse and human were 75%, 92% and 31%, respectively. Interspecies allometric scale-up predictions of human CL (41 ml/h/kg), CLu (467 ml/h/kg) and Vss (3.3 L/kg) were similar to reported values, whereas poor predictions of human Vuss (33 L/kg), Vdarea (4.1 L/kg) and T0.5 (3 days) were obtained. Conclusions. Insignificant accumulation in humans inspite of the long terminal T0.5 was rationalized to be due to the small terminal-phase area contribution. While human CL and Vss were sucessfully predicted in the interspecies scaling, poor predictions of human Vdarea and T0.5 were obtained, which was attributed to disposition pattern differences between humans and other species, a potential new critical factor affecting interspecies scale-up.
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    URL: http://dx.doi.org/10.1023/A:1011923704731
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  • 30
    Electronic Resource
    Electronic Resource
    Immediate and Long-Term Effects of 5,7-Dihydroxytryptamine on Rat Striatal Serotonergic Neurons Measured Using In Vivo Voltammetry (1998)
    Springer
    Neurochemical research 23 (1998), S. 1-6 
    Details
    ISSN: 1573-6903
    Keywords: 5,7-Dihydroxytryptamine ; intracerebroventricular administration ; serotonin release ; in vivo voltammetry ; pharmacokinetics ; striatum
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The immediate and long-term effects of the selective serotonergic neurotoxin 5,7-dihydroxytryp-tamine (5,7-DHT) on rat striatal serotonergic neurons were examined after its intracerebroventricular administration using in vivo voltammetry. Extracellular concentration of 5-hydroxyindoles increased immediately following intracerebroventricular 5,7-DHT injection (200 μg in 24 μl, 18 min), peaked at 1.5-2 h, and returned to normal by 4 h. 5,7-DHT diffused to the contralateral striatum in detectable amounts 9 to 12 min after the start of injection and returned to basal levels by 1.5 h. Three to 6 days after 5,7-DHT lesions, 5-hydroxytryptophan administration produced an increase in striatal 5-hydroxyindoles that was greater than that produced in pre-lesioned rats. This effect was maximal at 14 to 17 days post-lesion, and remained even after 50 days. The short-term effect of 5,7-DHT may be attributable to increased serotonin release, inhibition of uptake, or monoamine oxidase inhibition. The long-term effect of 5,7-DHT lesions may attributable to increased synthesis of serotonin or decreased reuptake in remaining serotonergic neurons.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1022460216822
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  • 31
    Electronic Resource
    Electronic Resource
    Nephrologic complications of drug therapy in the elderly (1998)
    Springer
    Geriatric nephrology and urology 8 (1998), S. 29-44 
    Details
    ISSN: 1573-7306
    Keywords: aged ; contrast sensitivity ; drug toxicity ; hyperkalemia ; pharmacokinetics ; renal failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008203008239
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  • 32
    Electronic Resource
    Electronic Resource
    Guide for judicious use of the paracetamol absorption technique in a study of gastric emptying rate of liquids (1998)
    Springer
    Journal of gastroenterology 33 (1998), S. 785-791 
    Details
    ISSN: 1435-5922
    Keywords: Key words: gastric emptying rate ; paracetamol (acetaminophen) ; pharmacokinetics ; rate of absorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract: The paracetamol absorption technique, a widely used method for evaluating the gastric emptying rate of liquids, appears to be performed inappropriately, resulting from a lack of consideration of pharmacokinetics in paracetamol absorption. This review suggests that appropriate study designs and logical choice of the parameters for the rate of paracetamol absorption are the cornerstone of reliable investigation of gastric emptying using the paracetamol method.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s005350050177
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  • 33
    Electronic Resource
    Electronic Resource
    A phase I and pharmacokinetic trial of terephthalamidine (NSC 57155) as a 120-hour continuous infusion (1998)
    Springer
    Investigational new drugs 16 (1998), S. 57-67 
    Details
    ISSN: 1573-0646
    Keywords: phase I ; pharmacokinetics ; terephthalamidine ; NSC 57155 ; phthalanilides
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract In this phase I study, terephthalamidine was administered as a 120-hour continuous infusion repeated every 21 days. Thirteen patients received 27 courses of terephthalamidine at four dose levels (14, 28, 46, and 70 mg/m2/day). Dose-limiting toxicity consisted of profound and intractable anorexia, weight loss and prostration in all patients. Toxicity was delayed and accompanied by hyponatremia and hypokalemia. No hematologic or other toxicity was documented. One patient with adenocarcinoma of the lung had a 40% decrease in mediastinal lymph nodes and resolution of a pleural effusion lasting 2 months. Pharmacokinetic analysis by HPLC was performed in all patients during their first course. The harmonic mean terminal half-life for terephthalamidine was 23 hours with a plasma clearance of 1.7 l/hr/m2. Both plasma concentrations achieved during infusion (r2 = 0.9) and area under the curve (AUC) (r2 = 0.8) were proportional to increase in dose (p 〈 0.002). Renal excretion accounted for 64% of the total cumulative dose, with an average renal clearance of 1.16 l/hr/m2. Due to the unacceptable toxicity seen at all doses with this schedule, no further studies are recommended unless the mechanism of toxicity is better understood and can be prevented.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006003718255
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  • 34
    Electronic Resource
    Electronic Resource
    Effect of Particle Size and Charge on the Disposition of Lipid Carriers After Intratumoral Injection into Tissue-isolated Tumors (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 128-132 
    Details
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; tissue-isolated tumor ; liposome ; emulsion ; intratumoral injection
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Pharmacokinetic properties of various lipid carriers (liposome and emulsions) after intratumoral injection were studied in perfusion experiments using tissue-isolated tumor preparations of Walker 256 carcinosarcoma. Methods. Four types of lipid carriers, large emulsion (254 nm), small emulsion (85 nm), neutral liposomes (120 nm) and cationic liposomes (125 nm) were prepared. We quantified their recovery from the tumor, leakage from the tumor surface and venous outflow after intratumoral injection into perfused tissue-isolated tumors, and analyzed venous appearance curves based on a pharmacokinetic model. Results. In contrast to the small emulsion and neutral liposomes, which immediately appeared in the venous outflow perfusate following intratumoral injection, the appearance of the cationic liposomes and the large emulsion was highly restricted, clearly demonstrating that intratumoral clearance of these formulations can be greatly retarded by the cationic charge and large particle size, respectively. The venous appearance rate-time profiles were fitted to equations derived from a two-compartment model by nonlinear regression analysis. When the calculated parameters were compared among these four formulations, the venous appearance rate did not exhibit such a large difference; however, the rate of transfer from the injected site to the compartment which involves clearance by venous outflow was all very different. Conclusions. The results of this study indicate that the determining factor which alters the pharmacokinetic properties of these lipid carriers after intratumoral injection is not the rate of transfer from the interstitial space to the vascular side but the rate of intratumoral transfer from the injection site to the well-vascularized region.
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    URL: http://dx.doi.org/10.1023/A:1011921324952
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  • 35
    Electronic Resource
    Electronic Resource
    Estimation of Oral Bioavailability of a Long Half-Life Drug in Healthy Subjects (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1782-1786 
    Details
    ISSN: 1573-904X
    Keywords: bioavailability ; pharmacokinetics ; squalene synthase inhibitor ; prodrug
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To estimate and compare the oral bioavailability of a drug (BMS-187745) administered as single doses of oral solution of either the parent drug or its prodrug (BMS-188494). Methods. A single-dose, two-period, three-treatment, control-balanced, residual-effect, incomplete block crossover study was completed in 16 healthy male subjects. All subjects received a 10 mg IV infusion of BMS-187745, and a single oral dose of either BMS-187745 (PO1) or BMS-188494 (PO2). A model is proposed to calculate the oral bioavailability of BMS-187745 which has a long half-life; incomplete data points were available to characterize its elimination phase. The plasma concentration-time data obtained following IV infusion of parent drug, and after administration of either PO1 or PO2 treatment were fitted simultaneously with systemic pharmacokinetic parameters shared by both the oral and IV routes of administration. Results. The best simultaneous fittings of the plasma concentration-time data were obtained by using a biexponential pharmacokinetic model with a first-order absorption rate constant. The mean bioavailability (F) values of BMS-187745 estimated by the proposed model were 26.5% and 2.6% when given as oral solution of its prodrug and as the parent drug. The coefficient of variation (CV) of these F values are reasonable, ranging from 38−40%. In contrast, F calculated by the model-independent AUC method exhibited high CV, ranging from 111−120%. Conclusions. The oral bioavailability values estimated by the proposed model were more reasonable compared to those calculated by the model-independent AUC method. The proposed approach may be useful for estimating bioavailability of long half-life drugs when incomplete data points are available to characterize their elimination phase.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011977116543
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  • 36
    Electronic Resource
    Electronic Resource
    Risedronate Gastrointestinal Absorption Is Independent of Site and Rate of Administration (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 228-232 
    Details
    ISSN: 1573-904X
    Keywords: risedronate ; gastrointestinal absorption ; gastrointestinal site ; bisphosphonate ; administration rate ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Two studies were conducted to compare the absorption of risedronate administered as a solution to three different gastrointestinal sites (study A) and to determine the extent of absorption of risedronate solution administered by rapid and slow infusion to the second part of the duodenum (study B). Methods. Each study was designed as a single-dose, crossover (three periods, study A; two periods, study B) trial in healthy male subjects, with a 14-day washout period between dosing. Subjects fasted overnight before drug administration and for 4 hours after drug administration. In study A, a risedronate solution of 40 mg in 30 mL of water was administered directly into the stomach, the second part of the duodenum, or the terminal ileum over 1 minute via a nasoenteral tube in a three-period crossover design. In study B, a risedronate solution of 40 mg in 30 mL of water was administered directly into the second part of the duodenum over 1 minute and over 1 hour in a randomized, two-period crossover design. Serum and urine samples were obtained for 48 hours after dosing for risedronate analysis. Results. Eight subjects completed each study. No statistically significant site-specific differences in any pharmacokinetic parameter were observed (study A). Based on the area under the serum concentration-time profile and the amount of drug excreted in the urine unchanged, the extent of risedronate absorption did not differ significantly following a rapid or a slow infusion (study B). Only minor symptomatic complaints were reported by subjects, such as headaches and body aches. Conclusions. These studies indicate that the rate and extent of risedronate absorption are independent of the site of administration along the gastrointestinal tract, and that the extent of absorption is not affected by the rate of administration.
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    URL: http://dx.doi.org/10.1023/A:1011910517200
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  • 37
    Electronic Resource
    Electronic Resource
    Use of the Stable Isotopes Technique to Evaluate the Bioavailability of a Pharmaceutical Form of Magnesium in Man (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 347-351 
    Details
    ISSN: 1573-904X
    Keywords: magnesium ; absolute bioavailability ; stable isotopes ; pharmacokinetics ; ICP-MS
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011947525377
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  • 38
    Electronic Resource
    Electronic Resource
    Blood-Brain Barrier Equilibration of Codeine in Rats Studied with Microdialysis (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 570-575 
    Details
    ISSN: 1573-904X
    Keywords: microdialysis ; codeine ; morphine ; blood-brain barrier ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The purpose of the study was to investigate the distribution of codeine across the blood-brain barrier (BBB) in rats by micro-dialysis (MD). Methods. Rats were administered intravenous infusion of codeine in doses of (1) 10 mg/kg, (2) 20 mg/kg for 10 min, and (3) an exponential infusion for 2 h aiming at a plasma concentration of 2500 ng/ml, in a crossover design (n = 6). Microdialysis was used to determine codeine unbound concentrations in blood and brain extracellular fluid (ECF). Total brain tissue and plasma concentrations were also determined. Nalorphine was used as a calibrator for measurement of in vivo recovery. Results. Relative recovery and retrodialysis loss of codeine and nalorphine were similar both in vitro and in vivo. Codeine was rapidly transported into the brain ECF with identical influx and efflux clearance across the BBB. The AUC ratios of brain to blood were 0.99 ± 0.25 and 0.95 ± 0.16 for Dose 1 and 2, respectively. The Css ratio of brain to blood was 1.06 ± 0.12 for the exponential infusion. The half-lives were 25 ± 4 min, 22 ± 2 min in blood and 27 ± 5 min, 25 ± 5 min in brain for Dose 1 and Dose 2, respectively. Total brain tissue concentrations were 3.6 ± 1.2-fold higher than the unbound concentrations in brain. Codeine was demethylated to morphine with an unbound AUCbIood,morphine/AUCblood,codeine ratio of 7.7 ± 5.1% in blood. No morphine was detected in brain MD, but total concentrations were possible to measure. Conclusions. Codeine rapidly reached a distributional equilibrium with equal unbound concentrations in blood and brain. The brain transport of codeine did not show any dose-dependency.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011929910782
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  • 39
    Electronic Resource
    Electronic Resource
    Pulmonary Bioavailability of a Phosphorothioate Oligonucleotide (CGP 64128A): Comparison with Other Delivery Routes (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 583-591 
    Details
    ISSN: 1573-904X
    Keywords: administration ; antisense ; bioavailability ; gastrointestinal ; intra-peritoneal ; intra-tracheal ; ISIS 3521 ; oligonucleotide ; oral ; pharmacokinetics ; subcutaneous
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Phosphorothioate antisense oligodeoxynucleotides are promising therapeutic candidates. When given systemically in clinical trials they are administered via slow intravenous infusion to avoid their putative plasma concentration-dependent haemodynamic side-effects. In this study, we have evaluated alternative parenteral and non-parenteral administration routes which have the potential to enhance the therapeutic and commercial potential of these agents. Methods. The delivery of CGP 64128A by intravenous, subcutaneous, intra-peritoneal, oral and intra-tracheal (pulmonary) routes was investigated in rats using radiolabelled compound and supported by more specific capillary gel electrophoretic analyses. Results. Intravenously administered CGP 64128A exhibited the rapid blood clearance and distinctive tissue distribution which are typical for phosphorothioate oligodeoxynucleotides. Subcutaneous and intra-peritoneal administration resulted in significant bioavailabilities (30.9% and 28.1% over 360 min, respectively) and reduced peak plasma levels when compared with intravenous dosing. Administration via the gastrointestinal tract gave negligible bioavailability (〈2%). Intra-tracheal administration resulted in significant but dose-dependent bioavailabilities of 3.2, 16.5 and 39.8% at 0.06, 0.6 and 6.0 mg/kg, respectively. Conclusions. Significant bioavailabilities of CGP 64128A were achieved following subcutaneous, intra-peritoneal and intra-tracheal administration. Pulmonary delivery represents a promising mode of non-parenteral dosing for antisense oligonucleotides. The dose-dependent increase in pulmonary bioavailability suggests that low doses may be retained in the lungs for local effects whereas higher doses may be suitable for the treatment of a broader spectrum of systemic diseases.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011934011690
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  • 40
    Electronic Resource
    Electronic Resource
    Skin Mini-Erosion Sampling Technique: Feasibility Study with Regard to Serial Glucose Measurement (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 883-888 
    Details
    ISSN: 1573-904X
    Keywords: transdermal access ; skin erosion ; transdermal ; dermal interstitial fluid ; sampling ; glucose ; monitoring ; diabetes mellitus ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To describe a dermally non-invasive serial sampling technique and to test its clinical feasibility with regard to glucose measurement. Methods. A standardized skin mini-erosion devoid of the epidermal barrier, and covered by an artificial one, was formed by a suctioning technique. Interstitial fluid (IF) was extracted serially by brief application of negative pressure, and its glucose content compared with that in capillary or venous blood samples. Results. The procedure caused no discomfort. The epidermis regenerated rapidly after experimentation. There were no complications. In non-diabetic subjects (n = 13) the mean of all IF values measured daily for 6 days was 6.2 ± 0.1 mmol/1 (±SE). The corresponding capillary blood glucose value was 5.6 ± 0.1 mmol/1, and the venous glucose value was 5.4 ± 0.1 mmol/1. The differences between IF glucose values and invasive control values remained within narrow limits throughout. The 2SD limits of agreement for the differences were 1.44 mmol/1 (IF vs. capillary blood samples) and 1.76 mmol/1 (IF vs venous samples) respectively. The OGTT curves suggested glucose kinetics to be similar in IF and in capillary blood. In diabetic subjects, the mean of IF values determined serially during one day was 15.3 ± 1.0 mmol/1 (range, 6.7−21.8 mmol/1), and the corresponding mean capillary value was 12.0 ± 0.9 mmol/1 (range, 3.3−17.2 mmol/1). The ICC for all paired photometric observations was 0.948. Conclusions. The results suggest the new sampling technique to be a feasible approach for clinical and experimental purposes. A functionally integrated sampling patch is entering the clinical testing stage.
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    URL: http://dx.doi.org/10.1023/A:1011924631680
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  • 41
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and Biodistribution of a Nucleotide-Based Thrombin Inhibitor in Rats (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 904-910 
    Details
    ISSN: 1573-904X
    Keywords: GS522 ; oligodeoxynucleotide ; pharmacokinetics ; tritiated ; biodistribution ; rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To characterize the pharmacokinetic and tissue distribution profiles of a nucleotide-based thrombin inhibitor (GS522, phosphodiester oligonucleotide, GGTTGGTGTGGTTGG) following intravenous administration to rats. Methods. Pharmacokinetic study: 10 mg/kg, 20 mg/kg, 30 mg/kg (6 animals/dose) were administered to rats by rapid injection into the femoral vein. Blood samples were collected over a 45 minute period. Plasma concentrations of GS522 were determined using capillary gel electrophoresis with laser-induced fluorescence detection. Biodistribution Study: l0mg/kg (400μl, 31.46 μCi/ml) of 3H-GS522 was administered to rats by rapid injection into the femoral vein. The animals were sacrificed by decapitation at 1, 5, 10, 30, 60, 360 minutes post-dose (3 rats/point). Brain, blood, duodenum, eyes, heart, kidney, liver, lungs, muscle, pancreas, skin, spleen and vein samples were collected, processed and quantitated using liquid scintillation counting. Results. The pharmacokinetic profile declines in multiexponential manner, exhibiting extremely fast distribution and elimination (t1/2 = 7.6−9.0 min, Cl = 22.0−28.0 ml/min, V = 83.9−132.4 ml/kg). GS522 follows linear pharmacokinetics, with the area under the curve being proportional to the dose (Rsq = 0.9744). Highest radioactivity levels were detected in kidney, liver and blood (39.7, 15.7 and 15.3% dose/ respective organ). Less than 1% of the dose was detected in the heart, spleen and lungs, and 〉0.3% of the dose was found in the brain and eyes. The oligonucleotide associated radioactivity was uniformly distributed between the brain regions (left and right lobe and cerebellum). Six hours following the dose administration a statistically significant increase (p 〈 0.05) in radioactivity levels was observed in the brain, eyes, skin, liver, pancreas and vein. Conclusions. The pharmacokinetic and biodistribution profiles of GS522 following intravenous administration to rats at three doses were characterized. The oligonucleotide associated radioactivity was widely distributed in tissues. The amount of radioactivity sharply decreased with time in most tissues. Kidney, liver and muscle were the main sites of accumulation. The oligonucleotide associated radioactivity did not cross the blood brain barrier to an appreciable extent. In addition, a statistically significant increase (p 〈 0.05) in the radioactivity levels observed in select tissues suggested a re-uptake mechanism for intact oligonucleotide or its degradation products.
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    URL: http://dx.doi.org/10.1023/A:1011980716659
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  • 42
    Electronic Resource
    Electronic Resource
    Lack of In Vivo/In Vitro Correlations for 50 mg and 250 mg Primidone Tablets (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1085-1089 
    Details
    ISSN: 1573-904X
    Keywords: primidone ; bioavailability ; human ; pharmacokinetics ; in vitro dissolution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To determine if large differences in the in vitro dissolution profiles for primidone tablets would result in significant bioavailability differences. Methods. Two separate bioavailability studies were conducted. The first study used 18 healthy subjects and compared the bioavailability of an old 50 mg tablet formulation, a new 50 mg tablet formulation, and a suspension containing 50 mg/ml of primidone. The second study enrolled 24 subjects who were to receive a new 250 mg tablet formulation, two lots of an old 250 mg tablet formulation and a 250 mg tablet from a second manufacturer. In vitro dissolution was conducted over 90 minutes, using USP 23 Apparatus 2 at 50 rpm, with 900 ml of water. Results. Dissolution at 90 minutes for the old and new 50 mg tablets was approximately 20% and 100%, respectively. The dissolution of the four 250 mg tablets ranged from approximately 30% to 100%. The 50 mg tablet that dissolved slower had a longer Tmax and a 14% lower Cmax than the more rapidly dissolving tablet, but the AUC(0−∞) values differed by only 3%. Only nine subjects completed the 250 mg study because of side effects. The differences in Cmax and AUC(0−∞) among the four 250 mg tablets were less than 7%. Conclusions. Even though there were large differences in the in vitro dissolution of the 50 mg and the 250 mg primidone tablets, the two 50 mg tablets were shown to be bioequivalent, as were the four 250 mg tablets.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011942530288
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  • 43
    Electronic Resource
    Electronic Resource
    Guar Gum-Based Sustained Release Diltiazem (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1196-1201 
    Details
    ISSN: 1573-904X
    Keywords: guar gum ; sustained release ; extended release ; diltiazem ; dissolution ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. This study was performed to examine the use of guar gum to sustain the release of diltiazem under in vitro and in vivo conditions. Methods. Guar gum tablet formulations were prepared and evaluated under a variety of in vitro dissolution conditions. The formulations, along with Dilacor XR®, were administered to a group of eight fasted, healthy volunteers in a four period crossover study. Results. Varying the lot of guar gum as well as using guar from different suppliers had little effect on diltiazem dissolution. Also, dissolution of diltiazem from guar gum tablets was essentially independent of stir speed under normal conditions (USP Apparatus II). The stability of guar-based formulations under stressed conditions (40°C/75% relative humidity for 3 months) was also established. All four formulations gave similar plasma concentrations over time in the healthy volunteers pharmacokinetic study. Conclusions. Guar gum-based matrix tablets represent a simple and economical alternative to existing diltiazem sustained release dosage forms.
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    URL: http://dx.doi.org/10.1023/A:1011931622536
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  • 44
    Electronic Resource
    Electronic Resource
    Pharmacokinetic and Pharmacoimmunodynamic Interactions Between Prednisolone and Sirolimus in Rabbits (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1888-1894 
    Details
    ISSN: 1573-904X
    Keywords: prednisolone ; sirolimus ; immunosuppressant ; interaction ; pharmacokinetics ; pharmacodynamics ; rabbit
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To assess pharmacokinetic and pharmacoimmunodynamic interactions between prednisolone (Pred, 1 mg/kg) and sirolimus (Sir, 0.25 mg/kg) in rabbits. Methods. After intravenous administration, plasma concentrations of Pred and corticosterone, and Sir blood concentrations were followed for 24 hours along with blood granulocyte and T-helper cell counts. Ex vivo and in vitro whole blood lymphocyte proliferation marked lymphocyte reactivity. Results. Pred terminal half-life and clearance were 1.1 hr and 0.72 l/ hr/kg with no difference after Sir. Sir values were 13 hr and 0.16 1/hr/ kg and Pred produced no changes. Corticosterone production (0−12hr) was suppressed by 55% after Pred alone or combined, while Sir did not cause adrenal suppression. Blood T-helper cells and granulocytes displayed circadian rhythms after placebo. Over 12 hr, T-helper cell counts were decreased by Pred (40%) and Sir (19%) while granulocyte numbers increased by 56% and 23%. After coadministration, cell numbers were similar to Pred alone. Pred and Sir decreased lymphocyte reactivity by 41% and 56% over 24 hr and their combination reached 85% inhibition with additive interaction. In vitro studies showed antagonistic or synergistic interactions depending on drug concentration ratios. Conclusions. At therapeutic concentrations, Sir and Pred do not significantly interact pharmacokinetically and have additive pharmacoimmunodynamics. Thus, the therapeutic application of this combination is promising.
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    URL: http://dx.doi.org/10.1023/A:1011966308791
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  • 45
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and Leukocyte Responses of Recombinant Human Interleukin-10 (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1895-1901 
    Details
    ISSN: 1573-904X
    Keywords: IL-10 ; cytokines ; protein ; immunosuppression ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To study the pharmacokinetics and ex vivo leukocyte responses of recombinant human IL-10 (rHuIL-10) following single SC and IV dosing. Methods. A randomized two-way cross-over study was undertaken in 17 healthy volunteers in which rHuIL-10 was administered as 25 μg/ kg SC and IV doses. Blood samples were collected for 48 hr after dosing to determine serum IL-10 concentrations. Inhibitory activity of IL-10 on ex vivo production of inflammatory cytokines (TNF-α and IL-1β) by LPS-treated peripheral blood cells were measured over 96 hr. Results. A physiologically-relevant modeling approach was developed to determine the pharmacokinetics for two routes of administration (SC and IV). The IV dose showed polyexponential disposition with CL of 65 mL/kg/hr, Vss of 70 mL/kg, and t1/2 of 1.94 hr. Absolute bioavailability averaged 42% for SC dosing which produced lower but sustained concentrations. Substantial and prolonged suppression of TNF-α and IL-1β production was achieved during IL-10 treatment. The Hill Function was used to account for the joint concentration-dependent immunosuppressive action of rHuIL-10 after both IV and SC doses. The IC50 values were about 0.03 ng/mL and Imax values were about 0.85 for both TNF-α and IL-lβ suppression. The degree of change as well as the duration of leukocyte response was greater after SC administration than after IV administration. Conclusions. rHuIL-10 shows favorable PK/PD characteristics especially by theSC route of administration which produced prolonged suppression of cytokine production (ex vivo) which may be applicable in various immune-related disorders.
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    URL: http://dx.doi.org/10.1023/A:1011918425629
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    Electronic Resource
    Influence of Different Fat Emulsion-Based Intravenous Formulations on the Pharmacokinetics and Pharmacodynamics of Propofol (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 442-448 
    Details
    ISSN: 1573-904X
    Keywords: propofol ; pharmacokinetics ; pharmacodynamics ; rats ; EEG ; fat emulsion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The influence of different intravenous formulations on the pharmacokinetics and pharmacodynamics of propofol was investigated using the effect on the EEG (11.5-30 Hz) as pharmacodynamic endpoint. Methods. Propofol was administered as an intravenous bolus infusion (30 mg/kg in 5 min) or as a continuous infusion (150 mg/kg in 5 hours) in chronically instrumented male rats. Propofol was formulated as a 1% emulsion in an Intralipid 10%®-like fat emulsion (Diprivan-10®, D) or as a 1%- or 6% emulsion in Lipofundin® MCT/LCT-10% (Pl% and P6%, respectively). EEG was recorded continuously and arterial blood samples were collected serially for the determination of propofol concentrations using HPLC. Results. Following bolus infusion, the pharmacokinetics of the various propofol emulsions could adequately be described by a two-compart-mental pharmacokinetic model. The average values for clearance (Cl), volume of distribution at steady-state (Vd,ss) and terminal half-life (t1/2, λ2) were 107 ± 4 ml/min/kg, 1.38 ± 0.06 l/kg and 16 ± 1 min, respectively (mean ± S.E., n = 22). No significant differences were observed between the three propofol formulations. After continuous infusion these values were 112 ± 11 ml/min/kg, 5.19 ± 0.41 l/kg and 45 ± 3 min, respectively (mean±S.E., n = 20) with again no statistically significant differences between the three propofol formulations. Comparison between the bolus- and the continuous infusion revealed a statistically significant difference for both Vd,ss and t1/2, λ2 (p 〈 0.05), whereas Cl remained unchanged. In all treatment groups infusion of propofol resulted in a burst-suppression type of EEG. A profound hysteresis loop was observed between blood concentrations and EEG effect for all formulations. The hysteresis was minimized by a semi-parametric method and resulted in a biphasic concentration-effect relationship of propofol that was described non-parametrically. For P6% a larger rate constant onset of drug effect (t,1/2, keo) was observed compared to the other propofol formulations (p〈0.05). Conclusions. The pharmacokinetics and pharmacodynamics of propofol are not affected by to a large extent the type of emulsion nor by the concentration of propofol in the intravenous formulation.
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  • 47
    Electronic Resource
    Electronic Resource
    Effect of GF120918, a Potent P-glycoprotein Inhibitor, on Morphine Pharmacokinetics and Pharmacodynamics in the Rat (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 599-605 
    Details
    ISSN: 1573-904X
    Keywords: morphine ; morphine-3-glucuronide ; P-glycoprotein ; pharmacokinetics ; pharmacodynamics ; antinociception ; central nervous system ; analgesia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The objective of this study was to evaluate the effect of a potent P-gp inhibitor, GF120918, on the systemic pharmacokinetics and antinociceptive pharmacodynamics of a single intravenous dose of morphine in rats. Methods. Male Sprague-Dawley rats received either 500 mg base/kg/d GF120918 or vehicle for 4 days by gavage, or no pretreatment. On day 4, morphine was administered as a 1- or 2-mg/kg i.v. bolus. Antinociception, expressed as percent of maximum possible response (%MPR), was evaluated over 300 min after morphine administration. Serial blood samples were collected and analyzed for morphine and morphine-3-glucuronide (M3G) by HPLC. Results. Morphine clearance and distribution volume were not altered significantly by GF120918. M3G AUC in the GF120918-treated rats was approximately 2-fold higher than in vehicle-treated rats. For both morphine doses, %MPR and the area under the effect-time curve at 300 min were significantly higher in the GF120918-treated rats. A pharmacokinetic/pharmacodynamic effect model accurately described the effect-concentration data for the rats that received 1-mg/kg morphine; ke0 was significantly smaller for GF 120918- vs. vehicle-treated and control rats (0.060 ± 0.028 vs. 0.228 ± 0.101 vs. 0.274 ± 0.026 min−1, p=0.0023). EC50 and γ were similar between treatment groups. Conclusions. Pretreatment with GF 120918 enhanced morphine antinociception, as assessed by the hot-lamp tail-flick assay, and elevated systemic M3G concentrations in rats. The differential pharmacologic response to morphine in the GF120918-treated animals could not be attributed to alterations in systemic morphine pharmacokinetics.
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    URL: http://dx.doi.org/10.1023/A:1011938112599
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  • 48
    Electronic Resource
    Electronic Resource
    Receptor Occupancy in Myocardium, Adrenal Cortex, and Brain by TH-142177, a Novel AT1 Receptor Antagonist in Rats, in Relation to Its Plasma Concentration and Hypotensive Effect (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 911-917 
    Details
    ISSN: 1573-904X
    Keywords: angiotensin II receptor antagonist ; TH-142177 ; rat tissues ; ex vivo receptor occupancy ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To study the relationship between angiotensin II (All) receptor occupancy ex vivo in tissues plasma concentration and hypotensive effect of a novel All receptor antagonist, TH-142177 and losartan in rats. Methods. At 2, 8 and 24 hr after oral administration of TH-142177 and losartan in rats, All receptors in myocardium, adrenal cortex and cerebral cortex were determined by radioligand binding assay using [125I]Sar1,Ile8-AII. Plasma concentrations of both drugs and metabolite in rats were also measured using validated HPLC assays. Further, systolic blood pressure (SBP) in conscious renal hypertensive rats treated orally with TH-142177 and losartan were measured by using a tail cuff plethysmographic method. Results. Oral administration of TH-142177 (1.8 and 5.5 μmol/kg) and losartan (6.5 and 21.7 μmol/kg) in rats brought about dose-dependent decreases in [125I]Sar1,Ile8-AII binding sites (Bmax) in myocardium and adrenal cortex. The extent of receptor occupancy by both drugs in adrenal cortex was maximal at 2 hr later but that in myocardium at 8 hr later. Further, the receptor occupancy was more sustained in myocardium than adrenal cortex. The ex vivo binding affinity of TH-142177 for All receptors in these tissues was roughly three times higher than that of losartan. Also, cerebral cortical [125I]Sar1,Ile8-AII binding was significantly reduced by oral administration of losartan but not by TH-142177. The time course of All receptor occupancy by both drugs in adrenal cortex appeared to be in parallel with that of their plasma concentrations, while the time course in myocardium correlated with that of their hypotensive effects rather than plasma concentrations. Conclusions. TH-142177 produced a relatively selective and sustained occupancy ex vivo of All receptors in myocardium and adrenal cortex of rats with approximately three times greater potency than losartan. Its time course of myocardial receptor occupancy was in parallel with that of hypotensive effect rather than plasma concentration.
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  • 49
    Electronic Resource
    Electronic Resource
    Correction for Non-Ideal Tracer Pharmacokinetic Disposition by Disposition Decomposition Analysis (DDA) (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1469-1473 
    Details
    ISSN: 1573-904X
    Keywords: drug tracer ; labeling ; pharmacokinetics ; erythropoietin ; iodination
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Pharmacokinetic (PK) studies assume that the tracer's PK is equivalent to the parent compound. This assumption is often violated. The aim of this work is to present a method enabling the ideal tracer PK, i.e. the PK of the parent compound, to be predicted from the non-ideal tracer. Methods. The procedure uses a disposition decomposition-recomposition (DDR) that assumes that the labeling mainly changes the elimination kinetics while the distribution kinetics is not significantly affected. In the DDR procedure an elimination rate constant correction factor (kCOR) is determined from a simultaneously fitting to plasma concentration data resulting from an i.v. injection of both the tracer and the parent compound. The correction factor is subsequently used to predict the ideal tracer PK behavior from the disposition function (i.v. bolus response) of the non ideal tracer. Results. The DDR method when applied to plasma level data of erythropoietin (r-HuEPO) and its iodinated tracer (l25I-r-HuEPO) from a high (4000U/kg) and a low (400U/kg) dosing of r-HuEPO in newborn lambs (n = 13) resulted in excellent agreements in the elimination rate corrected dispositions in all cases (r = 0.995, SD = 0.0095). The correction factor did not show a dose dependence (p 〉 0.05). The correction factors were all larger than 1 (kCOR = 1.94, SD = 0.519) consistent with a reduction in the EPO elimination by the iodination labeling. Conclusions. The DDR tracer correction methodology produces a better differentiation of the PK of endogenously produced compounds by correcting for the non-ideal PK behavior of chemically produced tracers.
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    URL: http://dx.doi.org/10.1023/A:1011922209757
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  • 50
    Electronic Resource
    Electronic Resource
    Correlation of Plasma Clearance of 54 Extensively Metabolized Drugs Between Humans and Rats: Mean Allometric Coefficient of 0.66 (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1474-1479 
    Details
    ISSN: 1573-904X
    Keywords: plasma clearance ; unbound plasma clearance ; inter-species scale-up in plasma clearance ; allometric analysis ; pharmacokinetics ; rat vs. human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To evaluate the distribution of allometric exponents for relationship of total plasma clearance of 54 extensively metabolized drugs, with wide-ranging linear clearance values, between humans and rats, to provide a rationale for the observed data, and to discuss potential significance of the findings. Methods. Human and rat plasma clearance values of 54 drugs with markedly different physicochemical properties were obtained from the literature. Standard allometric analysis was performed for each drug using both rat and human data. Unbound vs. total plasma clearances were obtained for 15 out of 54 drugs and their correlations between humans and rats were compared. Results. The mean ± SD of the allometric exponent for the 54 drugs studied is 0.660 ± 0.190. The median clearance ratio based on unit body weight is 7.41 and the median exponent is 0.645. Excluding two outliers the correlation coefficient of plasma clearance between humans and rats was 0.745 (p 〈 0.0001). For the 15 drugs, use of unbound plasma clearance approach seems to significantly improve the correlation coefficient compared to total plasma clearance (0.940 vs. 0.841). Conclusions. The present study indicates that on average, humans and rats may eliminate extensively metabolized drugs at a rate similar to that expected from the allometric or body surface area relationship of basal metabolic rate between the two species. A simple statistical distribution hypothesis is used to rationalize the species difference in plasma drug clearance. Rat may serve as an useful animal model to predict (unbound) plasma clearance of drugs in humans.
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    URL: http://dx.doi.org/10.1023/A:1011974226596
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  • 51
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    Electronic Resource
    Combined Use of Carboxyl-Directed Protein Pegylation and Vector-Mediated Blood-Brain Barrier Drug Delivery System Optimizes Brain Uptake of Brain-Derived Neurotrophic Factor Following Intravenous Administration (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 576-582 
    Details
    ISSN: 1573-904X
    Keywords: pegylation ; blood-brain barrier ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Peptide drug delivery to the brain requires optimization of (a) plasma pharmacokinetics and (b) blood-brain barrier (BBB) permeability. In the present studies, plasma pharmacokinetics are improved with protein pegylation and BBB transport is facilitated with the use of vector-mediated drug delivery using the OX26 monoclonal antibody (MAb) to the rat transferrin receptor, which undergoes receptor-mediated transcytosis through the BBB in vivo. Methods. A conjugate of OX26 and streptavidin (SA), designated OX26/SA, was prepared in parallel with the carboxyl-directed pegylation of brain-derived neurotrophic factor (BDNF). A novel bifunctional polyethyleneglycol (PEG) was used in which a hydrazide (Hz) was attached at one end and a biotin moiety was attached to the other end. This allowed for conjugation of BDNF-PEG-biotin to OX26/SA. Results. The brain uptake of BDNF-PEG-biotin was increased following conjugation to OX26/SA to a level of 0.144 ± 0.004% injected dose per g brain and a BBB permeability-surface area product of 2.0 ± 0.2 μL/min/g. Conclusions. These studies demonstrate that peptide drug delivery to the brain can be achieved with advanced formulation of protein-based therapeutics. The formulation is intended to (a) minimize rapid systemic clearance of the peptide, and (b) allow for vector-mediated drug delivery through the BBB in vivo. Following this dual formulation, the brain uptake of a neurotrophin such as BDNF achieves a value that is approximately 2-fold greater than that of morphine, a neuroactive small molecule.
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    URL: http://dx.doi.org/10.1023/A:1011981927620
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  • 52
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    Electronic Resource
    Preliminary observations on the pharmacokinetics of CDRI compound 81/470 in calves (1998)
    Springer
    Veterinary research communications 22 (1998), S. 67-72 
    Details
    ISSN: 1573-7446
    Keywords: anthelmintic ; benzimidazole ; calf ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005939328885
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  • 53
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    Electronic Resource
    The disposition kinetics of albendazole following the administration of single and divided doses to cattle and buffalo (1998)
    Springer
    Veterinary research communications 22 (1998), S. 87-96 
    Details
    ISSN: 1573-7446
    Keywords: anthelmintic ; albendazole ; buffalo ; cattle ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Concentrations of albendazole sulphoxide and its sulphone metabolite in plasma in cattle and buffalo were measured by high-performance liquid chromatography after single and divided intraruminal administration of albendazole at the recommended nematocidal and fasciolicidal dose rates of 7.5 and 15.0 mg/kg body weight, respectively. No significant differences in the plasma concentrations of the metabolites or their pharmacokinetic parameters were observed between cattle or buffalo at either dose rate. Pharmacokinetic analysis and the disposition curve of the metabolites indicated increased uptake of the drug in both cattle and buffalo when the same total amount of the drug was given in divided doses compared to a single dose (p〈0.05). The divided dose schedules of administration could possibly be exploited to extend the life of the available benzimidazole anthelmintics.
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    URL: http://dx.doi.org/10.1023/A:1006023328617
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  • 54
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    Electronic Resource
    The effect of feed quality on the kinetic disposition of orally administered triclabendazole in sheep (1998)
    Springer
    Veterinary research communications 22 (1998), S. 257-263 
    Details
    ISSN: 1573-7446
    Keywords: anthelmintics ; Fasciola ; nutrition ; pharmacokinetics ; sheep ; triclabendazole
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effect of two qualities of feed on the kinetic disposition of triclabendazole (TCBZ) metabolites was investigated in sheep (n = 4) following oral administration of TCBZ at 10 mg/kg body weight. The same sheep were given sequentially two qualitatively different diets: a low-quality (LQ) diet based on wheat straw ad libitum, and a high-quality (HQ) diet based on barley+alfalfa. The triclabendazole sulphoxide (TCBZSO) and triclabendazole sulphone (TCBZSO2) concentrations were determined in blood samples taken serially from the jugular vein between 5 min and 9 days after TCBZ administration. The parent drug TCBZ was not detected in any of the samples. The quality of feed affected the kinetics of both TCBZ metabolites. The rate of appearance (Tlag and Tmax) in the jugular blood was slower and the formed amount (AUC) of TCBZSO was slightly higher when the sheep were on the LQ diet (Tlag = 7.74 h; Tmax = 27.91 h; AUC = 1042 μg.h/ml) than when they were offered the HQ diet (Tlag = 1.90 h; Tmax = 16.01 h; AUC = 832.4 μg.h/ml). The MRT of TCBZSO was about 40% longer with the LQ diet than with the HQ diet. Similarly, the rate of appearance of TCBZSO2 in plasma of sheep was slower when they were on the LQ diet than when they were on the HQ diet, suggesting an impairment of the hepatic enzymatic activity involved in the oxidation of TCBZSO to TCBZSO2.
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    URL: http://dx.doi.org/10.1023/A:1006095400309
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  • 55
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    Electronic Resource
    Pharmacokinetics of antipyrine in rats with different resistance to hypoxia in cold stress (1998)
    Springer
    Bulletin of experimental biology and medicine 126 (1998), S. 1098-1099 
    Details
    ISSN: 1573-8221
    Keywords: pharmacokinetics ; antipyrine ; individual resistance to hypoxia ; cold stress
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract It is shown that the parameters of antipyrine pharmacokinetics during cold exposure depend on individual resistance to hypoxia. High-resistant rats are characterized by less intense metabolism and more rapid normalization of pharmacokinetic parameters than lowresistant rats characterized by shortened elimination half-time corresponding to a more rapid metabolism of xenobiotics under conditions of cold stress.
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    URL: http://dx.doi.org/10.1007/BF02447243
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  • 56
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    Electronic Resource
    Preliminary evaluation of potential anti-epileptic drugs by single dose electrophysiological and pharmacological studies in patients (1988)
    Springer
    Journal of neural transmission 72 (1988), S. 259-266 
    Details
    ISSN: 1435-1463
    Keywords: Anti-epileptic drugs ; pharmacokinetics ; EEG ; photosensitivity ; drug interactions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In phase 1 evaluation of potential anti-epileptic drugs (AEDs), insufficient attention has perhaps been directed to the transition from single, and multi-dose studies in normal volunteers to clinical trials of some weeks duration in patients. Acute single dose studies in epileptic patients already receiving AEDs may reduce avoidable errors in early controlled trials. Acute single dose studies provide the opportunity of obtaining some preliminary evidence of efficacy by observing the effects of the drug on quantified epileptiform EEG discharges, both those occurring spontaneously in long term telemetric recordings and those elicited by standardised photic stimulation in susceptible subjects. The pharmacokinetics of the new drug may be profoundly influenced by the comedication (as illustrated by lamotrigine, the half life of which varies by a factor of 10 depending on comedication). Conversely, the new drug may so influence metabolism of the comedication that the results of add-on trials may be virtually uninterpretable, unless steps are taken to maintain blood levels of the other AEDs. A method of addressing this problem is illustrated in the case of an imidazole, R 57720. Adverse experiences may also occur more readily when a new drug is added to comedication than when it is given to normal volunteers and these problems in chronic trials can be anticipated from acute studies.
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    URL: http://dx.doi.org/10.1007/BF01243424
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  • 57
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    Electronic Resource
    Comparative pharmacokinetics of ceftazidime in young, healthy and elderly, acutely ill males (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 179-186 
    Details
    ISSN: 1432-1041
    Keywords: ceftazidime ; pharmacokinetics ; elderly patients ; young volunteers ; acute infection
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of ceftazidime have been investigated after single and multiple i.v. doses in 9 young healthy male volunteers and 15 elderly male patients with acute bacterial infections. All subjects had normal, age-correlated glomerular function. Distribution and elimination in young volunteers were unaffected by posture and were similar to what has been reported earlier. In contrast, elderly patients had longer t1/2β (3.1 vs 1.9 h), larger AUC (414.0 vs 276.6 h·mg/l), lower total and renal clearances, reduced urinary recovery over 12 h and enlarged Vss. Total serum clearance of ceftazidime was closely correlated with the51Cr-EDTA clearance. There was no significant change in51Cr-EDTA clearance after seven days of treatment. A reduction in the dose of betalactam antibiotics eliminated by the kidney is advisable in elderly patients with an acute bacterial infection.
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    URL: http://dx.doi.org/10.1007/BF00614556
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  • 58
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    Electronic Resource
    Pharmacokinetics and bioavailability of reduced and oxidized N-acetylcysteine (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 77-82 
    Details
    ISSN: 1432-1041
    Keywords: N-acetylcysteine ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and bioavailability of N-acetylcysteine (NAC) have been determined after its intravenous and oral administration to 6 healthy volunteers. According to a randomized cross-over design each subject received NAC 200 mg i.v. and 400 mg p.o., and blood samples were collected for 30 h. Reduced NAC had a volume of distribution (VSS) of 0.59 l·kg−1 and a plasma clearance of 0.84 l·h−1·kg−1. The terminal half-life after intravenous administration was 1.95 h. The oral bioavailability was 4.0%. Based on total NAC concentration, its volume of distribution (VSS) was 0.47 l·kg−1 and its plasma clearance was 0.11 l·h−1·kg−1. The terminal half-life was 5.58 h after intravenous administration and 6.25 h after oral administration. Oral bioavailability of total NAC was 9.1%.
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    URL: http://dx.doi.org/10.1007/BF01061422
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  • 59
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    Electronic Resource
    A preliminary study of the pharmacodynamics and pharmacokinetics of a novel enkephalin analogue [Tyr-D.Arg-Gly-Phe(4NO2)·Pro·NH2 (BW443C)] in healthy volunteers (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 67-71 
    Details
    ISSN: 1432-1041
    Keywords: BW443C ; enkephalin ; opioid peptide ; healthy volunteers ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied 16 healthy men to evaluate preliminary pharmacodynamics and kinetics of BW443C given by i.v. infusions. Four volunteers received escalating doses at weekly intervals, starting at 0.1 µg·kg−1 for 60 min and increasing to a maximum of 2.0 µg·kg−1·min−1 for 180 min. Subsequently 12 different subjects received single i.v. infusions of 10 µg·kg−1·min−1 for 20 min. Subjective effects were reported and objective measurements made of central nervous and cardiovascular effects. Blood was sampled at intervals on all occasions, plasma concentrations were determined by radioimmunoassay and pharmacokinetic profiles were analysed using NONLIN. Dry mouth and some nasal stuffiness were reported and postural hypotension occurred in 5/16 subjects at plasma concentrations 〉0.8 µg·ml−1. Supine blood pressure was well maintained in all subjects and hypotension resolved within 60–90 min of discontinuing the infusion. There was no evidence of sedation, mood change, nausea, vomiting, miosis, change in accomodation or respiratory depression. Rapid infusions produced transient feelings of warmth, heavy eyelids, heavy legs, and increased bowel sounds, which resolved despite increasing plasma concentrations. The disposition of the peptide was adequately described by a 2-compartment model with a mean ± SD plasma clearance of 123±18 ml·min−1 and a half-life of 2.0±0.4 h.
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    URL: http://dx.doi.org/10.1007/BF01061420
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  • 60
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of oxcarbazepine and 10-hydroxy-carbazepine in the newborn child of an oxcarbazepine-treated mother (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 311-313 
    Details
    ISSN: 1432-1041
    Keywords: oxcarbazepine ; newborns ; antiepileptic ; placental transfer ; 10-hydroxy-carbazepine ; pharmacokinetics ; breast milk transfer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Gaschromatography — mass spectrometry (GC/MS) was used to determine plasma levels of oxcarbazepine (OCB) and its main metabolite in a newborn girl and her OCB-treated mother during the first five post partum days. At delivery the maternal and neonatal plasma concentrations were in the same range, indicating considerable placental transfer of both substances. In spite of ingestion of both substances via breast milk, there was no accumulation in the baby. On the fifth post partum day OCB and 10-hydroxy-carbazepine (10-OH-CB) levels in plasma in the newborn were only 12 and 7%, respectively, of the values found on the first day after delivery.
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    URL: http://dx.doi.org/10.1007/BF00540963
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  • 61
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    The pharmacokinetics of doxifluridine and 5-fluorouracil after single intravenous infusions of doxifluridine to patients with colorectal cancer (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 439-443 
    Details
    ISSN: 1432-1041
    Keywords: doxifluridine ; colorectal carcinoma ; 5′-deoxy-5-fluorouridine ; 5-fluorouracil ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition kinetics of a new 5-fluorouracil prodrug, 5′-deoxy-5-fluorouridine (5′dFUR, doxifluridine), were investigated in six patients with colorectal carcinoma. Each patient randomly received two single intravenous doses of 5′dFUR (2 and 4 g · m−2) on separate days. Plasma concentrations of 5′dFUR fell rapidly with terminal half-lives ranging from 16.1 to 27.7 min. A disproportionate increase in the area under the curve with increasing dose was seen in most patients. Doubling the dose resulted in a 40% decrease in nonrenal clearance (0.60 to 0.37 l · min−1) but no apparent change in renal clearance (0.32 to 0.29 l · min−1) or steady-state apparent volume of distribution (19.8 to 20.4 l). The mechanism for dose-dependence of 5′dFUR appears to be primarily due to nonlinear elimination associated with nonrenal processes rather than nonlinear plasma protein or tissue binding.
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    URL: http://dx.doi.org/10.1007/BF01046699
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  • 62
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    Electronic Resource
    Kinetics and disposition of fluorescein-labelled liposomes in healthy human subjects (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 475-479 
    Details
    ISSN: 1432-1041
    Keywords: liposomes ; sodium fluorescin ; pharmacokinetics ; clinical studies ; drug delivery ; normals
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The in vivo kinetics and organ uptake of multilamellar liposomes have been studied in healthy volunteers. Sodium fluorescein-containing liposomes composed of equimolar amounts of egg phosphatidylocholine and cholesterol were injected into a peripheral vein in 4 healthy subjects. Blood samples collected from the femoral artery, hepatic vein and pulmonary artery, were analysed for liposomal dye content. The results, showing involvement of the reticuloendothelial system (RES) in the removal of liposomes, confirmed those previously obtained with radiolabelled preparations. Use of an innocuous liposomal marker (sodium fluorescein) and conventional vascular catheterization techniques, as employed here, may provide a reliable and clinically acceptable approach to establishing disease-induced changes in the kinetics of uptake of drug-containing liposomes by the RES, and thus help in the design of protocols for effective treatment.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01046705
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    Pharmacokinetics of xamoterol after intravenous and oral administration to volunteers (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 469-473 
    Details
    ISSN: 1432-1041
    Keywords: xamoterol ; cardiac failure ; beta1-adrenoceptor partial agonist ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of xamoterol, a β-adrenoceptor partial agonist under clinical evaluation for the treatment of mild to moderate heart failure, have been studied in 12 healthy male subjects. They received 14 mg i.v. and oral doses of 50 and 200 mg as a tablet and 200 mg as a solution in a 4 way cross-over design. After i.v. dosing the elimination half-life was 7.7 h, the total body clearance was 224 ml·min−1 and the volume of distribution at steady-state (Vss) was 48 l. Sixty-two percent of the dose was recovered unchanged in urine. After oral doses, the absolute bioavailability of xamoterol was shown to be 5% irrespective of whether the dose was administered as a tablet or solution. Peak plasma concentrations occurred at about 2 h for the tablet dose and slightly earlier (1.4 h) for the solution. Peak plasma concentration, AUC and urinary recovery of unchanged drug increased in proportion to dose. The apparent elimination half-life after oral doses (16 h) was significantly longer than that observed after an intravenous dose. Despite the low bioavailability, the degree of inter-subject variability of oral bioavailability was small probably indicating that the controlling factor is the hydrophilic nature of the molecule rather than extensive first pass metabolism or poor dissolution of xamoterol from the tablet formulation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01046704
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  • 64
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    Electronic Resource
    The effects of posture on the pharmacokinetics of intramuscular benzylpenicillin (1988)
    Springer
    European journal of clinical pharmacology 33 (1988), S. 629-635 
    Details
    ISSN: 1432-1041
    Keywords: benzylpenicillin ; posture ; intramuscular administration ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Previous reports have produced conflicting results as to whether changes in posture affected the pharmacokinetics of the penicillins. We have studied the pharmacokinetics of intramuscularly administered benzylpenicillin in normal subjects during bedrest and ambulation and compared it with data obtained following intravenous administration of the same dose to the same subjects under the same conditions. The values of area under the curve, total clearance, mean residence time and renal clearance found during ambulation were 1175 (min·min·l−1), 488 (ml·min−1), 101 (min), and 264 (ml·min−1) (means). The corresponding values for bedrest were 1032 (min·mg·l−1), 544 (ml·min−1), 96.7 (min), and 315 (ml·min−1). There was a significant difference between the areas under the curve with change of posture but not between any of the other pharmacokinetic variables. The differences observed in this study are unlikely to be of clinical relevance. We suggest that the differences between the results of this study and those of previous studies may be related to the level of exercise undertaken by the subjects in the various studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542500
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  • 65
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    Electronic Resource
    The disposition of biphenylacetic acid following topical application (1988)
    Springer
    European journal of clinical pharmacology 33 (1988), S. 639-642 
    Details
    ISSN: 1432-1041
    Keywords: biphenylacetic acid ; plasma and synovial fluid concentrations ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma and synovial fluid concentrations of biphenylacetic acid were determined following application of 3 g of 3% biphenylacetic acid gel to one knee of patients suffering from rheumatoid arthritis. The mean peak plasma concentration was 34 ng/ml. Synovial fluid concentrations tended to follow plasma concentrations but at a somewhat lower level, the mean peak synovial fluid concentration was 21 ng/ml. The average ratio of synovial fluid AUC (0–24 h) to plasma AUC (0–24 h) was 0.58, r=0.97. Where patients had bilateral effusions, the concentration in the ipsilateral knee at each time point examined was not significantly different to that in the contralateral knee, suggesting that absorption was initially into the plasma and subsequently into the synovium.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542502
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  • 66
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    Pharmacokinetic and pharmacodynamic properties of a new controlled-release formulation of metoprolol: A comparison with conventional tablets (1988)
    Springer
    European journal of clinical pharmacology 33 (1988), S. S9 
    Details
    ISSN: 1432-1041
    Keywords: metoprolol ; controlled-release formulation ; pharmacokinetics ; pharmacodynamics ; exercise heart rate ; healthy volunteers ; efficacy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic and pharmacodynamic properties of a new multiple-unit, controlled-release (CR) formulation of metoprolol1 (metoprolol succinate, 95 mg once daily), which has almost constant (zero-order) release properties over most of a 24-h dose interval, have been compared with those of conventional metoprolol tablets (metoprolol tartrate, 100 mg once daily and 50 mg twice daily), in 12 healthy male volunteers. The steady-state plasma concentrations of metoprolol after five days of treatment varied less throughout the day with the CR than with the conventional formulation. This was associated with a considerably lower peak plasma concentration and the achievement of a significantly higher plasma concentration at the end of the dose interval. Similarly, the effect on exercise-induced tachycardia was maintained at a relatively constant level throughout the day after treatment with the CR formulation. A significantly greater effect 24 h after administration was achieved with the CR formulation, when compared with once-daily dosing with metoprolol tablets, 100 mg. Twice-daily dosing with metoprolol tablets, 50 mg, produced a similar β1-blocking effect at the end of the dose interval to that observed with metoprolol CR. Although the steady-state plasma concentrations indicated significantly lower systemic availability for the CR formulation, compared with both regimens of metoprolol tablets, the total effect over the dose interval, expressed as the area under the efficacy curve (AUEC), was similar for the three treatments. The relationship between steady-state plasma concentrations and the pharmacodynamic efficacy at corresponding times, indicated that plasma concentrations were more effectively utilized after the administration of the CR formulation than after the conventional tablet regimens. The results of this study clearly indicate the potential benefits offered by the new metoprolol CR formulation, under all circumstances where a constant degree of β1-selective blockade, without plasma peaks and troughs, is preferred.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00578406
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  • 67
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    Electronic Resource
    Influence of once-monthly rifampicin and daily clofazimine on the pharmacokinetics of dapsone in leprosy patients in Nigeria (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 73-76 
    Details
    ISSN: 1432-1041
    Keywords: dapsone ; rifampicin ; clofazimine ; leprosy ; drug interaction ; multidrug therapy ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In leprosy patients in Nigeria the influence of daily clofazimine and of once-monthly rifampicin on the pharmacokinetics of dapsone has been investigated. Three days after rifampicin the elimination half-life of dapsone was reduced from 40.4 to 25.3 h (n=23). Correspondingly, the plasma dapsone 24 h after the last dose had fallen significantly from 2.63 to 2.02 mg/l. Clofazimine did not cause change in the pharmacokinetics of dapsone. It was concluded that, although rifamipicin had a considerable influence on the pharmacokinetics of dapsone, there is no reason to adjust the dose of dapsone during multidrug therapy of leprosy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01061421
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  • 68
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    Electronic Resource
    Influence of digestive secretions and food on intestinal absorption of nicardipine (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 165-171 
    Details
    ISSN: 1432-1041
    Keywords: nicardipine ; pharmacokinetics ; gastrointestinal absorption ; influence of food ; intestinal perfusion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The role of digestive absorption in the pharmacokinetics of nicardipine has been studied by the perfusion technique. Nicardipine (40 mg) was perfused in six healthy subjects at 5 ml/min for 2 h either in isotonic saline with (Experiment A) or without (B) an occlusive balloon isolating the test segment from digestive secretions, or in a nutrient solution (Experiment C). In Experiments A and B, 100% of nicardipine was absorbed from the jejunal lumen in a 25 cm test segment and in Experiment C it was slightly lower (94%). There was no relationship between the absorption of nicardipine and water movement or bile salt concentration in the jejunum. Nicardipine was already present in the first plasma sample taken after 15 min and the peak level was found at the end of the perfusion. The areas under the curves differed widely between subjects, because of interindividual variation in the first pass effect, but they were similar in Experiments A, B and C. The experimental data showed a good fit to a mode involving a two-phase absorption process. The first phase was associated with intestinal perfusion (zero order process) and the second with passage accross the intestinal wall (1st order process). In three further healthy subjects, nicardipine in saline was perfused in the jejunum and then in the ileum on consecutive days. Mean plasma levels over time were similar. The study showed that absorption of nicardipine both from the jejunum and the ileum was complete and was especially rapid. The food-induced change in the kinetics of absorption from the jejunum was too small to affect the pharmacokinetic parameters of nicardipine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00614554
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  • 69
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    Pharmacokinetics of nisoldipine in renal dysfunction (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 207-209 
    Details
    ISSN: 1432-1041
    Keywords: nisoldipine ; renal dysfunction ; pharmacokinetics ; blood pressure control
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of nisoldipine have been studied after oral administration of one 10 mg tablet to 3 groups of patients: Group A (n=8) with a mean creatinine of 90 ml/min, Group B (n=8) with a mean creatinine clearance of 12 ml/min and Group C of 12 patients on maintenance haemodialysis. All of them were studied off-dialysis and 7 were also studied on a dialysis day. No significant differences were observed between Groups A, B and C (on an interdialysis day) in AUC (0–7h), tmax, Cmax and plasma protein binding. Unchanged nisoldipine could not be recovered from the urine in any patient. Haemodialysis did not significantly affect AUC, tmax and Cmax, and nisoldipine could not be detected in the dialysate. The results indicate that the dose of nisoldipine need not be changed in patients with renal dysfunction, and that a supplementary dose is not required after haemodialysis. Blood pressure in the uraemics fell more than in the patients with good renal function.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00614560
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  • 70
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    Electronic Resource
    Single- and multiple-dose pharmacokinetics of terodiline in geriatric patients (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 291-297 
    Details
    ISSN: 1432-1041
    Keywords: terodiline ; elderly patients ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary As a target group, geriataric patients were selected for pharmacokinetic studies with terodiline (Mictrol), an anticholinergic and calcium antagonist drug effective in the treatment of urinary incontinence. The single-dose kinetics in the geriatric patients (mean age 82 years) differed significantly from that previously found (Hallén et al. 1987) in healthy volunteers (mean age 35 years). There were higher peak serum concentrations (110 vs 79 µg·l−1), increased half-life (189 vs 60 h), lower renal clearance (4.0 vs 10.9 ml·min−1) and lower total clearance (29 vs 75 ml·min−1). Multiple-doses of 12.5 mg b.d. for 6–8 weeks resulted in a mean steady-state concentration of 642 µg·l−1, which was in agreement with the single dose parameters. The studied geriatric patients can be characterized not only as old, but also as frail, bedridden, having several diseases and polymedicated. The differences in pharmacokinetics between younger and elderly subjects can be attributed to a variety of complex factors, which may alter the clearance and/or the volume of distribution.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00540958
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  • 71
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    The influence of cholestyramine on the elimination of tenoxicam and piroxicam (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 283-289 
    Details
    ISSN: 1432-1041
    Keywords: piroxicam ; tenoxicam ; cholestyramine ; accelerated drug elimination ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the influence of multiple oral doses of cholestyramine on the single dose pharmacokinetics of tenoxicam and piroxicam in eight healthy young volunteers. Each subject received on two occasions single intravenous injections of 20 mg tenoxicam and on another two occasions single oral doses of 20 mg piroxicam. Both medications were followed by multiple oral doses of either cholestyramine or plain water (placebo). Compared with placebo cholestyramine accelerated the elimination of both drugs. The average values of half-lives were reduced (tenoxicam: 31.9 h vs 67.4 h; piroxicam: 28.1 h vs 46.8 h) due to increases in clearance. Cholestyramine-mediated enhancement of drug elimination was most pronounced in the subjects with a comparatively low baseline drug clearance. Thus, intersubject variability in clearance was smaller when the drug administrations were followed by the anion-exchange resin. The twofold acceleration of tenoxicam elimination in the present study in man contrasts with a much larger effect (five-fold) seen in experiments with dogs. This points to a much easier access of unchanged tenoxicam to the intestinal lumen in the dogs than in man. Comparing the pharmacokinetics of tenoxicam and piroxicam in the same volunteers revealed a high degree of correlation in clearance and half-lives and similar intersubject variabilities in mean kinetic variables.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00540957
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  • 72
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    The pharmacokinetics of olsalazine sodium in healthy volunteers after a single i.v. dose and after oral doses with and without food (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 481-488 
    Details
    ISSN: 1432-1041
    Keywords: olsalazine sodium ; 5-ASA ; ac-5-ASA ; pharmacokinetics ; effect of food
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Olsalazine sodium (5,5′-azodisalicylic acid (OLZ)) was given to eight healthy volunteers as a 10 mg i.v. bolus dose and as a 1 g oral dose with and without food. To five fasting participants single oral doses of 2 g and 4 g were given. Blood and urine were collected during three weeks after each dose and were assayed for OLZ, a conjugate identified as a sulphate of OLZ (OLZs), 5-aminosalicylic acid (5-ASA), and N-acetyl-5-aminosalicylic acid (ac-5-ASA). The study showed that: 1. OLZ had a very short elimination half-life, mean 56 min. 2. OLZ was absorbed from the intestinal tract to a very small extent, as seen from the low systemic availability and low urinary excretion, 2.3% and 0.31% respectively, for a 1 g dose taken fasting. 3. OLZ was present in the serum partly as a conjugate, which was identified as an O-sulphate. Following the i.v. dose the serum half-life of the O-sulphate was estimated to be 7 days. 4. Food intake did not influence the systemic availability of OLZ and ac-5-ASA. 5. There was no dose-dependent increase of OLZ absorption with single doses up to 2 g, but a 4-g dose showed a more than two-fold increase in the individual peak serum concentration and in the systemic availability of OLZ. However, there was no significant increase in the mean residence time (MRT) for OLZ or in the serum concentration of either 5-ASA or ac-5-ASA at a dose of 4 g.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01046706
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  • 73
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    CSF and plasma pharmacokinetics of pethidine and norpethidine in man after epidural and intrathecal administration of pethidine (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 625-631 
    Details
    ISSN: 1432-1041
    Keywords: pethidine ; analgesics ; epidural-/intrathecal injection ; pharmacokinetics ; drug metabolism ; norpethidine ; adverse effects ; CSF drug levels
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition of pethidine and its main metabolite, norpethidine, in cerebrospinal fluid (CSF) and plasma was studied in 11 thoracic surgery patients after lumbar epidural (100 mg;n=6) or lumbar intrathecal (25 mg;n=5) administration of pethidine. Pethidine appeared more slowly in plasma after intrathecal than after epidural administration (tmax 2.3 h and 14 min, respectively), but systemic bioavailability was similar. The CSF concentrations of pethidine were higher than those in plasma after both routes of administration. The maximal CSF/plasma concentration ratio was 6000 to 45000 after intrathecal administration but was only 26 to 97 after the epidural route. Pethidine was rapidly distributed in CSF; nine to ten h after the intrathecal and epidural injections the CSF/plasma concentration ratios were 12 to 89 and 2 to 33, respectively. The calculated bioavailability in CSF of epidural pethidine was 10.3%. The terminal elimination half-life of pethidine was 6.0 h (CSF) and 5.4 h (plasma) after intrathecal administration and 8.6 h (CSF) and 8.8 h (plasma) after epidural injection. The volume of distribution of unchanged pethidine in the subarachnoid space was 13 ml·kg−1 and clearance from the CSF was 15 µl·kg−1·min−1. In all patients receiving intrathecal pethidine and in some patients after epidural pethidine, CSF norpethidine concentrations were higher than those in plasma; the maximum CSF norpethidine was 102 to 1211 ng·ml−1 and 14 to 210 ng·ml−1 and the maximum CSF/plasma norpethidine concentration ratios were 21 to 652 and 0.6 to 14 times after intrathecal and epidural administration, respectively. Norpethidine was rapidly distributed and its level in CSF was about the same or lower than in plasma during the terminal elimination phase. The maximum CSF norpethidine level was 1.2±1.0% of that of pethidine after intrathecal injection. Thus, epidural pethidine enters the CSF more rapidly and to a greater extent than has been previously shown for epidural morphine, but pethidine is more rapidly redistributed from CSF. The terminal elimination half-life of pethidine was found to be long in relation to the reported duration of analgesia after a single spinal dose of pethidine, which suggests a potential risk of accumulation within the CSF on multiple spinal injections of pethidine. Pethidine is partly metabolised within the subarachnoid space by N-dealkylating enzymes in the CNS. After intrathecal injection of more than 25 mg pethidine, the concentration of the principle metabolite, norpethidine, in CSF may be higher than that associated with CNS toxicity in man.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00615228
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  • 74
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    Electronic Resource
    Doxazosin in patients with hypertension (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 21-24 
    Details
    ISSN: 1432-1041
    Keywords: doxazosin ; hypertension ; alpha-adrenergic blockade ; bioavailability ; pharmacokinetics ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The antihypertensive effects and steady-state pharmacokinetics of doxazosin, as well as the bioequivalence of four dosage forms, were studied in 25 hypertensive patients. For an 8 mg daily dose mean Cmax at steady-state for all patients was 108 ng/ml; the mean tmax was 1.8 h. The mean terminal elimination half-life was 22 h. The four tablets containing 1, 2, 4, or 8 mg of doxazosin were bioequivalent in delivering the 8 mg dose. In patients with mild to moderate hypertension, 26-day treatment with doxazosin resulted in blood pressure reduction of 10/7 mm Hg in the supine and 13/18 mm Hg in the standing position. Adverse effects were generally mild and of brief duration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00555502
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  • 75
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    The absolute systemic availability of a new oral formulation of co-dergocrine in healthy subjects (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 53-57 
    Details
    ISSN: 1432-1041
    Keywords: codergocrine ; prolactin ; hydergine ; pharmacokinetics ; systemic availability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the absolute systemic availability (f) of an oral formulation (Hydergin spezial = Hydergine FASR 4 mg per tablet) of codergocrine by three different methods. Twelve healthy volunteers received single doses of 0.9 mg co-dergocrine intravenously and 8.0 mg orally in a randomized crossover design. The pharmacological effect of co-dergocrine was monitored as a reduction in plasma prolactin. Maximal plasma concentrations of co-dergocrine after oral dosing ranged between 0.181 and 1.307 ng·ml−1. Maximal urinary excretion ranged between 4.7 and 9.9 µg·h−1 and between 0.3 and 2.3 µg·h−1 after intravenous and oral doses respectively. Clearance was measured as 90±22 l·h−1 and the absolute systemic availability (f) as 2.25±0.65% by using the areas under the plasma concentration-time curves extrapolated to infinity. Calculation of f by comparing areas up to 32 h or the fractions of the dose excreted in urine led to identical results. The intravenous and oral doses produced similar pharmacological effects (reduction of plasma prolactin concentrations) despite the small value of f.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00555507
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  • 76
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    Lack of effect of cimetidine on the pharmacokinetics and metabolism of a single oral dose of metronidazole (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 65-68 
    Details
    ISSN: 1432-1041
    Keywords: metronidazole ; cimetidine ; pharmacokinetics ; drug interaction ; drug metabolism ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The time course of the effect of cimetidine on the pharmacokinetics of metronidazole was investigated in 6 healthy volunteers. Cimetidine 1.0 g/day was administered for 9-days and metronidazole 500 mg was administered orally on the second and eighth days, and in a control experiment. During cimetidine treatment the plasma kinetics of metronidazole and its partial clearance by renal excretion of the unchanged compound, glucuronidation, hydroxylation and oxidation to its acetic acid metabolite were not significantly different from the control values. The results indicate that cimetidine does not influence the pharmacokinetics or metabolism of a single oral dose of metronidazole.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00555509
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  • 77
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    Pharmacokinetics of bolus intravenous and oral doses of L-carnitine in healthy subjects (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 69-75 
    Details
    ISSN: 1432-1041
    Keywords: L-carnitine ; pharmacokinetics ; intravenous and oral doses ; bioavailability ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of single intravenous and oral doses of L-carnitine 2 and 6 g was studied in 6 healthy subjects on a low-carnitine diet. Carnitine was more rapidly eliminated from plasma after the 6 g dose. Comparing the doses, the t1/2β of the elimination phase (β) was 6.5 h vs 3.9 h, the elimination constant 0.40 vs 0.50 h−1 and the plasma carnitine clearance was 5.4 vs 6.11 · h−1 for the 2 g and 6 g doses, respectively, showing dose-related elimination. Saturable kinetics were not found. The apparent volumes of distribution after the two doses were not significantly different and were of the same order as the total body water. Urinary recoveries of the 2 g and 6 g doses were 70% and 82%, respectively, during the first 24 h. Following the oral doses, there was no significant difference between the areas under the plasma carnitine concentration-time curves. Urinary recovery was 8% and 4% for the 2 g and 6 g doses during the first 24 h. Oral bioavailability was 16% for the 2 g dose and 5% for the 6 g dose. The results suggest that the mucosal absorption of carnitine was already saturated by the 2 g dose.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00555510
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  • 78
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    Therapeutic doses of codeine have no effect on acetaminophen clearance or metabolism (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 109-111 
    Details
    ISSN: 1432-1041
    Keywords: acetaminophen ; codeine ; clearance ; metabolite formation ; glucuronidation ; pharmacokinetics ; healthy volunteers ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In nine healthy volunteers, the clearance and metabolism of acetaminophen 1000 mg i.v. was evaluated with and without two concomitant oral doses of codeine in order to investigate a possible interaction. Plasma acetaminophen was followed for 720 min and urine was collected for 24 h after each dose for determination of metabolites. When codeine was coadministered, the average total clearance of acetaminophen and its clearance by glucuronidation, sulphation and mercapturate formation were 0.58 to 1.12-times the control values. It is concluded that therapeutic doses of codeine do not influence the clearance or metabolism of acetaminophen.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00555519
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  • 79
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    The effect of hydralazine on steady-state plasma concentrations of metoprolol in pregnant hypertensive women (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 131-135 
    Details
    ISSN: 1432-1041
    Keywords: metoprolol ; hydralazine ; hypertension ; pregnancy ; pharmacokinetics ; drug interactions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the plasma concentrations levels of metoprolol after its twice daily administration in a dose of 50 mg for 4 days in ten, hypertensive pregnant women to the during monotherapy and in combination with 25 mg of hydralazine given twice daily. Hydralazine increased the median AUC and Cmax of metoprolol by 38% and 88% respectively, and decreased the tmax from 1.5 h to 1.0 h. Hydralazine had no effect on the plasma concentrations of alpha-OH-metoprolol. These results suggest that the effect of hydralazine on metoprolol plasma concentrations is primarily due to a reduction in first-pass elimination.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609241
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  • 80
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of xamoterol after intravenous and oral administration to patients with chronic heart failure (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 183-185 
    Details
    ISSN: 1432-1041
    Keywords: xamoterol ; cardiac failure ; beta1-adrenoceptor partial agonist ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of xamoterol, a β-adrenergic partial agonist under clinical evaluation for the treatment of mild to moderate heart failure, have been studied in 8 cardiac failure patients (NYHA Class II) of mean age 62 years. After i.v. dosing, the elimination half-life was 7.4±0.4 h, the total body clearance was 228±30 ml·min−1 and the volume of distribution at steady-state was 56±91. 72.5±4.3% of the dose was recovered unchanged in urine. After the oral dose, the absolute bioavailability of xamoterol was shown to be 5.9%. Peak plasma concentrations occurred 1 to 2.5 h after the oral dose. The apparent elimination half-life was significantly longer after oral doses (16±2 h) compared to that observed after an intravenous dose. Renal clearance of xamoterol exceeded glomerular filtration rate as measured by creatinine clearance. The pharmacokinetics of xamoterol in cardiac failure patients with good renal function (creatinine clearance 〉90 ml·min−1) were similar to published data in young healthy male volunteers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609250
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  • 81
    Electronic Resource
    Electronic Resource
    Intra- and inter-subject variation in the pharmacokinetics of indoramin and its 6-hydroxylated metabolite (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 195-198 
    Details
    ISSN: 1432-1041
    Keywords: indoramin ; 6-hydroxyindoramin ; pharmacokinetics ; concentration variability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Intra- and inter-subject variation in the kinetics of indoramin and its active metabolite 6-hydroxyindoramin have been studied in 5 young, healthy, male volunteers administered a single oral dose of the drug on 5 separate occasions. Inter-subject variation represented the main source of variability in indoramin plasma concentrations with, for example, the between-subjects sum of squares (a measure of the contribution to the total variability) representing around 97% of the total sum of squares for Cmax and AUC (0–24). Intra-subject and inter-subject coefficients of variation (C.V.s) were circa 20% and 100% respectively for both these parameters. Variability in 6-hydroxyindoramin concentrations was much lower and was approximately equally derived from intra- and inter-subject variation, with the C.V.s being approximately 44% for both Cmax and AUC (0–24). The results imply that the kinetic behaviour of indoramin within an individual will prove relatively consistent, despite widespread inter-subject variation, once an appropriate dosage regime has been established.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609252
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  • 82
    Electronic Resource
    Electronic Resource
    The pharmacokinetics of ceftazidime in patients with impaired renal function and concurrent frusemide therapy (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 273-279 
    Details
    ISSN: 1432-1041
    Keywords: ceftazidime ; frusemide ; pharmacokinetics ; renal insufficiency
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacokinetics of ceftazidime in 37 patients suffering from serious bacterial infections. All the patients had impairment of renal function and received moderate to high doses of frusemide concurrently. The doses of ceftazidime were given according to renal function as recommended by the manufacturer. Serum and urine samples were frequently collected, and drug concentrations measured by high performance liquid chromatography. The patients were grouped and evaluated according to renal function, mean (SD) creatinine clearances ranging from 70.1 (12.4) to 11.0 (3.2) ml·min−1. The pharmacokinetics of ceftazidime depended on renal function. A statistically significant increase in ceftazidime elimination half-life and decreases in urinary recovery, total body clearance, and renal clearance in proportion to the decrease in renal function were observed (p〈0.05). The apparent volume of distribution also increased, but not significantly (p〉0.05). A linear correlation was found between the total body and renal clearances of ceftazidime and creatinine clearance. The extrarenal clearance increased from 3.9 to 14.0 ml·min−1 with decreasing renal function. Concurrent treatment with ceftazidime and moderate to high doses of frusemide did not impair renal function and no evidence of nephrotoxicity was found.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00558265
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  • 83
    Electronic Resource
    Electronic Resource
    Does alpha1-acid glycoprotein reduce the unbound metabolic clearance of disopyramide in patients with renal impairment? (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 313-317 
    Details
    ISSN: 1432-1041
    Keywords: disopyramide ; alpha1-acid glycoprotein ; renal dysfunction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of disopyramide was studied in 15 patients with renal dysfunction (4 with pyelonephritis, 7 with glomerular nephritis and 4 with interstitial nephritis). The elimination rate constant of unbound disopyramide was 0.094 h−1 and CLu/f (unbound clearance divided by bioavailability) was 245 ml/min. Both the unbound renal clearance (CLR) and CLu/f were highly correlated with the creatinine clearance (CLCR). The apparent unbound metabolic clearance in the patients was approximately two-fold lower than that previously reported in normal subjects. The estimated unbound metabolic clearance in the renal dysfunction patients showed a significant negative correlation with the α1-acid glycoprotein (AAG) concentration and only a weak, non-significant correlation with CLCR. As AAG in the renal dysfunction subjects was increased in comparison with normal values, it is possible that AAG is a factor in the decrease in the apparent unbound metabolic clearance.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00558271
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  • 84
    Electronic Resource
    Electronic Resource
    The pharmacokinetics of theophylline and enprofylline in patients with liver cirrhosis and in patients with chronic renal disease (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 357-362 
    Details
    ISSN: 1432-1041
    Keywords: theophylline ; enprofylline ; liver cirrhosis ; renal failure ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacokinetics of theophylline and enprofylline in patients with liver cirrhosis, patients with chronic renal failure, and healthy subjects, and have assessed the predictive value of routine tests of liver function and renal function (creatinine clearance) for theophylline and enprofylline total body clearances. Theophylline clearance was significantly decreased in the patients with liver cirrhosis compared with both the patients with renal failure and the healthy subjects (the mean values in the three groups were 24, 47, and 46 ml·h−1·kg−1 respectively. Enprofylline clearance was significantly decreased in the patients with chronic renal failure, compared with both the patients with liver cirrhosis and the healthy subjects (the values in the three groups were 64, 250, and 289 ml·h−1·kg−1 respectively. There was a strong correlation between creatinine clearance and enprofylline clearance, while there was only a poor correlation between the liver function tests and theophylline clearance. It appears that in various clinical situations enprofylline elimination can be predicted more precisely than theophylline elimination, which may make the drug safer in clinical practice.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00561364
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  • 85
    Electronic Resource
    Electronic Resource
    The behaviorally active peptide ACTH 4-10: Measurement in plasma and pharmacokinetics in man (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 371-377 
    Details
    ISSN: 1432-1041
    Keywords: ACTH 4-10 ; radioimmunoassay ; plasma extraction ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A specific radioimmunoassay for the quantitative measurement of ACTH 4-10 and a procedure for its extraction from plasma have been developed. Its pharmacokinetics was studied in eight healthy male volunteers given ACTH 4-10 125 µg/kg body weight as a bolus i.v. injection, by infusion and intranasally. Following the i.v. bolus, plasma levels rapidly declined biexponentially, with half-lives of 0.39±0.05 min for the α-phase and 3.84 ± 1.5 min for the β-phase (mean±SD). The constant rate i.v. infusion yielded steady-state levels between 0.74 and 5.06 ng/ml plasma. Administered as intranasal spray, absorption of intact ACTH 4-10 was low and variable (maximal bioavailability 7.6%). The results are discussed in relation to the dose-dependent effects of ACTH 4-10 on the auditory evoked potential.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00561367
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  • 86
    Electronic Resource
    Electronic Resource
    The pharmacokinetics of bendazac-lysine and 5-hydroxybendazac, its main metabolite, in patients with hepatic cirrhosis (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 391-396 
    Details
    ISSN: 1432-1041
    Keywords: bendazac ; liver cirrhosis ; pharmacokinetics ; drug metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacokinetics of bendazac and its major metabolite, 5-hydroxybendazac, in 11 patients with hepatic cirrhosis after the oral administration of a single 500 mg tablet of bendazac-lysine, and compared them with those obtained from 10 healthy adults. The rate of absorption of bendazac, as assessed by tmax and Cmax, is similar in patients and in healthy subjects. The drug is eliminated mostly by metabolism in healthy adults, more than 60% of the dose being excreted in the urine as 5-hydroxybendazac and its glucuronide. Hepatic insufficiency impairs this metabolism, a two-fold decrease in apparent plasma clearance (CL/f) being observed in the patients. Although the plasma unbound fraction of bendazac is increased in patients (the drug is highly bound to plasma albumin), the apparent volume of distribution (V/f) is unchanged. In consequence, the half-life of bendazac is increased two-fold in the patients. Impairment of metabolism decreases the formation of 5-hydroxybendazac, but metabolism remains the main route of its elimination. Renal excretion of bendazac accounts for about 10% of the dose in both patients with cirrhosis and healthy subjects. We conclude that in patients with severe hepatic insufficiency the daily dose of bendazac-lysine should be havled.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00561370
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  • 87
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of ketorolac tromethamine in humans after intravenous, intramuscular and oral administration (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 423-425 
    Details
    ISSN: 1432-1041
    Keywords: ketorolac tromethamine ; non-narcotic analgesic ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of ketorolac tromethamine, a potent non-narcotic analgesic agent used for relief of moderate to severe pain, has been studied in 15 healthy volunteers who received single 10 mg doses intravenously (i.v.), intramuscularly (i.m.) and orally (p.o.) in a three-way cross-over design. The kinetics of i.v. ketorolac were characterized by a terminal half-life of 5.09 h, a small plasma clearance (CL = 0.35 ml·min−1·kg−1) and a small tissue distribution (Vss=0.111·kg−1, Vβ=0.17 l·kg−1; mean (SD). Following i.m. and p.o. administration, peak levels of approximately 0.8 µg/ml were rapidly attained (tmax = 0.8 and 0.9 h, respectively) and the systemic bioavailability was essentially complete.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00561376
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  • 88
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of ranitidine in patients undergoing haemofiltration (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 427-430 
    Details
    ISSN: 1432-1041
    Keywords: ranitidine ; haemofiltration ; renal failure ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of ranitidine was investigated in 11 patients with acute or end stage renal failure during haemofiltration. Each patient received 50 mg ranitidine i.v. The mean distribution and elimination half lives were 0.13 and 2.57 h, respectively. The total body clearance (CL) and volume of distribution (Vz) were 298 ml·min−1 (5.19 ml·min−1·kg−1) and 1.081·kg−1, respectively. About 17.1% of the administered dose was removed by haemofiltration (in approximately 201 filtrate). Five of the patients still had some urine output and they excreted 0.1 to 11.8% of the dose in urine in 24 h. The haemofiltration clearance was 66.9 ml·min−1 at a filtrate flow rate of 86 ml·min−1, corresponding to a mean sieving coefficient of 0.78 (n=6). As plasma concentrations were still in an effective range after haemofiltration, dose supplementation is not recommended.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00561377
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  • 89
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of a new sublingual formulation of temazepam (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 437-439 
    Details
    ISSN: 1432-1041
    Keywords: temazepam ; formulations ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of a new 10 mg sublingual tablet formulation of temazepam and those of a currently marketed 10 mg oral capsule formulation were evaluated in a group of ten healthy volunteers. No significant differences were observed between the two formulations with respect to any of the pharmacokinetic parameters assessed. Lethargy and somnolence were reported on both capsule and tablet by several subjects at a time which corresponded with the maximum concentration of drug in plasma. The data indicate that the sublingual tablet and orally administered capsule have a similar pharmacokinetic and pharmacodynamic profile.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00561380
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  • 90
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of streptomycin in Ethiopian children with tuberculosis and of different nutritional status (1988)
    Springer
    European journal of clinical pharmacology 33 (1988), S. 647-649 
    Details
    ISSN: 1432-1041
    Keywords: streptomycin ; tuberculosis ; malnutrition ; pharmacokinetics ; children
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Fifty-six malnourished Ethiopian children with tuberculosis classified in four nutrional groups (normal, underweight, marasmus and kwashiorkor), were given streptomycin 20 or 30 mg·kg−1 i.m. The plasma concentration-time data revealed an increased apparent volume of distribution in children with kwashiorkor compared to normals. The total plasma clearance was low and did not differ between the nutrional groups. Thus, the half-life was prolonged only in kwashiorkor. The results could be explained by decreased protein binding in plasma and decreased renal clearance by glomerular filtration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542504
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  • 91
    Electronic Resource
    Electronic Resource
    Design of a new multiple-unit controlled-release formulation of metoprolol — Metoprolol CR (1988)
    Springer
    European journal of clinical pharmacology 33 (1988), S. S3 
    Details
    ISSN: 1432-1041
    Keywords: metoprolol ; controlled-release formulation ; pharmacokinetics ; plasma concentration profile
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A new controlled-release (CR) formulation of the β1-selective adrenoceptor antagonist metoprolol1 has been developed, aiming at an even 24-h pharmacological effect. In order to achieve this, using a once-daily dose, factors such as absorption characteristics, physicochemical properties, and technological aspects had to be considered. The new formulation, called metoprolol CR, is a disintegrating tablet consisting of several hundred coated pellets of metoprolol succinate, each pellet being its own CR delivery unit. In vitro testing and in vivo studies in healthy volunteers show that the new CR formulation gives continuous delivery of metoprolol throughout the day, resulting in smooth plasma concentration profiles, without peaks and troughs. The release of the drug is independent of pH and other physiological variables, such as food intake, which do not seem to alter the biopharmaceutical properties of the formulation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00578405
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  • 92
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of lisinopril in hypertensive patients with normal and impaired renal function (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 61-65 
    Details
    ISSN: 1432-1041
    Keywords: lisinopril ; renal failure ; half-life ; drug dose ; pharmacokinetics ; hypertension
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of lisinopril was studied after administration of single and multiple doses of 5 mg to hypertensive patients with normal and impaired renal function. In patients with severe renal failure the peak concentrations were higher, the decline in serum concentration was slower and the time to peak concentration was extended. Accumulation of lisinopril was highly correlated with the creatinine clearance. The effective half-life was doubled and tripled in patients with mild and severe renal impairment, respectively, as compared to patients with a normal renal function. Lisinopril lowered blood pressure in all three groups over 24 h. It is suggested that smaller doses of lisinopril should be administered to patients with severe renal failure.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01061419
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  • 93
    Electronic Resource
    Electronic Resource
    Single-dose and multiple-dose pharmacokinetics of etintidine in healthy volunteers (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 101-104 
    Details
    ISSN: 1432-1041
    Keywords: etintidine ; pharmacokinetics ; single-dose ; multiple-dose
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The present study was designed to determine the single- and multiple-dose pharmacokinetic profiles of the H2 receptor antagonist etintidine in healthy volunteers. Etintidine was rapidly absorbed and eliminated after the oral administration of 300 mg base equivalent of etintidine HCl in a capsule formulation to 11 healthy subjects. Comparison of the pharmacokinetics after a single dose and during steady state showed no significant differences (p〉0.05) in the mean values of Cmax, tmax, oral clearance, elimination rate constant, and renal clearance, indicating no significant accumulation of etintidine and no apparent time-dependent changes in the pharmacokinetics of etintidine during multiple dose administration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01061428
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  • 94
    Electronic Resource
    Electronic Resource
    Influence of food on the pharmacokinetics of dipyrone (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 105-107 
    Details
    ISSN: 1432-1041
    Keywords: dipyrone ; methylaminoantipyrine ; food interaction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Twelve healthy volunteers were given a single oral dose of dipyrone 1 g, once while fasting and once after a standard breakfast. Plasma levels of the active dipyrone metabolite — Methylaminoantipyrine (MAA) were measured and the calculated pharmacokinetic parameters were compared. Taking dipyrone with food resulted in a small delay in the mean time to peak from 1.5 h to 1.9 h (p〈0.01). However, there was no significant difference in AUC, Cmax or Kelim between fasting and nonfasting conditions. The rate of absorption, expressed as the mean Kabs, was somewhat slower in the nonfasting state, but not significantly so. It is suggested that dipyrone may be taken regardless of the times of eating.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01061429
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  • 95
    Electronic Resource
    Electronic Resource
    A double-blind and cross-over comparison of once daily doxazosin and placebo with steady-state pharmacokinetics in elderly hypertensive patients (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 119-123 
    Details
    ISSN: 1432-1041
    Keywords: doxazosin ; hypertension ; alpha1-adrenoceptor inhibitor ; elderly patients ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The α1-adrenoceptor antagonist doxazosin has been compared with placebo in 40 elderly hypertensive patients (mean age 71.4 years). At the end of 10 weeks once daily treatment with doxazosin the mean 24-h post-dose changes in standing and supine blood pressure compared with placebo were −6.9/−5.6 mmHg (systolic/diastolic) and −6.2/−5.5 mmHg respectively. The reductions in standing and supine diastolic blood pressures were statistically significant compared with placebo. At the end of treatment steady-state pharmacokinetics were evaluated in 18 patients. The plasma elimination half-life during the dose interval in these patients was 16.1 h (range 10.1–27.1 h) and the median time to peak plasma concentration was 3 h (range 1–4 h). One patient was withdrawn because of adverse effects (headache, weakness, and sweating) during doxazosin treatment. Once daily doxazosin reduced diastolic blood pressure and was well tolerated in these elderly hypertensive patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00614546
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  • 96
    Electronic Resource
    Electronic Resource
    Effect of probenecid on the elimination and protein binding of ceftriaxone (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 151-156 
    Details
    ISSN: 1432-1041
    Keywords: ceftriaxone ; probenecid ; drug interaction ; protein binding ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics and binding parameters of ceftriaxone have been characterized in eight normal subjects who received, in sequence, 1.0 g ceftriaxone and 1.0 g ceftriaxone together with 250 and 500 mg probenecid q.i.d. Probenecid increased the total systemic clearance (CL S T ) from 0.244 to 0.312 ml/min/kg, whereas the terminal half-life (t 1/2(β) T ) fell from 8.1 to 6.5 h. In contrast, the renal clearance of free ceftriaxone (CL R F ) was decreased from 2.09 to 1.67 ml/min/kg, confirming a small but significant contribution of tubular secretion to the renal elimination of ceftriaxone. The final value of CL R F was attained with the lower dose probenecid, whereas the non-renal clearance of free ceftriaxone (CL NR F ) fell progressively from 2.78 to 1.90 ml/min/kg with the increasing probenecid dose. The total decrease in the systemic clearance of free ceftriaxone (CL S F ) after the higher dose of probenecid was about 30% (4.87 to 3.57 ml/min/kg). As a consequence of a decreased affinity constant (KA), the average free fraction in plasma (f) was increased by 54% after the low dose and by 74% after the high dose of probenecid. The protein binding interaction between probenecid and ceftriaxone appears to be unique. The results are of limited clinical consequence for ceftriaxone but they emphasise the importance of evaluating the kinetics of the free drug when examining interactions involving probenecid.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00614552
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  • 97
    Electronic Resource
    Electronic Resource
    Influence of age on the pharmacokinetics of ceftazidime in acutely ill, adult patients (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 173-178 
    Details
    ISSN: 1432-1041
    Keywords: ceftazidime ; pharmacokinetics ; age dependency ; elderly patients ; acute infection
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The single and multiple i.v. dose pharmacokinetics of ceftazidime were investigated in 37 acutely ill patients with normal age-related glomerular function. Distribution was rapid with similar t1/2a at all ages. Compared to the younger patients, elderly subjects had lower total and renal clearances and reduced urinary recovery. Ceftazidime clearance was closely correlated with glomerular function. The t1/2β was approximately 2 h in young and middle-aged patients, 2.73 h in patients aged 60–79 years, and 3.54 h in those above 80 years. The AUC was more than doubled in the oldest patients compared to individuals younger than 40 years. Vss did not change with advancing age, but was larger than previously reported in healthy volunteers. Elimination variables were not altered during multiple dosing, but a small but significant increase in AUC was detected in the elderly. Dose reduction by 50% in patients more than 70 years old is suggested.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00614555
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  • 98
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and pharmacodynamics of propafenone during acute and chronic administration (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 187-194 
    Details
    ISSN: 1432-1041
    Keywords: propafenone ; 5-OH-propafenone ; antiarrhythmic effect ; pharmacokinetics ; chronic treatment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of propafenone and 5-OH-propafenone and their relationship with the antiarrhythmic action and side effects have been studied in 10 patients with stable, frequent, premature ventricular beats (224–928 premature ventricular complexes/h). Observations were made after a single dose of propafenone 300 mg p.o., and after 1 and 3 months (only 5 out of 10 patients) of therapy with 300 mg t.d.s. After 1 month of treatment the plasma elimination half-life of propafenone (6.7 h) was almost twice as long as after a single dose (3.5 h), and the area under the plasma propafenone concentration-time curve (7620 ng·ml−1·h) was significantly larger than after single dose (3522 ng·ml−1·h); this was also true for the metabolite. The ratio of the AUCs of 5-OH-propafenone and propafenone decreased from the single dose (0.63) to 1 month (0.32). These variables remained stable up to 3 months. Eight patients had ≧75% reduction of premature ventricular complexes after 3 days of therapy, and in 7 they were completely suppressed; the response was maintained over 1 to 3 months. Side effects were minor and in no case had the drug to be withdrawn or the dose reduced. Thus, the kinetics of propafenone were time-dependent. Its active metabolite did not accumulate greatly during chronic treatment. The lasting antiarrhythmic effect observed in some patients suggests a b.d.s. regimen instead of t.d.s. dosing in selected patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00614557
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  • 99
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and safety of l-carnitine infused i. v. in healthy subjects (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 213-216 
    Details
    ISSN: 1432-1041
    Keywords: carnitine ; i. v. infusion ; pharmacokinetics ; healthy subjects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and safety of a brief i. v. infusion of l-carnitine 0, 20, 40 and 60 mg/kg have been investigated in 10 healthy subjects. The diurnal intraindividual variability of plasma carnitine was small (C. V.=3.0, 3.9 and 3.9%, respectively), and the total 24 h excretion in urine was also small and relatively constant: 4.6, 21.5 and 13.0 mg/day in the controls vs 4.6, 20.2 and 6.0 mg/day during treatment in the three subjects to whom saline alone was administered according to a single-blind design. Therefore, the pre-dose level of carnitine was subtracted from the level after dosing for the pharmacokinetic analysis. Plasma carnitine fitted well to a three-compartment open model, with Vc of 0.11–0.20 l/kg and a t1/2γ of 10–23 h. The urine recovery in 24 h was 77.2–95.4%. There were no objective or subjective side-effects attributable to carnitine, so its i. v. infusion is considered to be safe.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00614562
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    Electronic Resource
    Electronic Resource
    Single and multiple dose pharmacokinetics of tenoxicam in the elderly (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 563-566 
    Details
    ISSN: 1432-1041
    Keywords: tenoxicam ; pharmacokinetics ; elderly ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Fourteen elderly subjects (10 women, 4 men) with a mean age of 81 (SD 6.7) years and in need of anti-inflammatory drug treatment were given a single dose of 20 mg tenoxicam. After a drug-free interval of 5 weeks, multiple dose treatment with 20 mg tenoxicam once daily for 56 days was initiated. The single and multiple dose kinetics of tenoxicam were investigated after HPLC determination of tenoxicam in the plasma. The elimination half-life of tenoxicam ranged from 44 to 132 h (mean 71.9 h) with no significant difference between the single and multiple dosage regimens. Tenoxicam reached maximum plasma concentrations after 1.4 and 1.1 h, with values of 3.6 and 15.5 µg·ml−1, for the single and multiple dosage regimen respectively. The corresponding trough values (24-h values) were 1.8 and 11.7 µg·ml−1. A mean accumulation ratio of 5.1 was calculated. The mean increase in the area under the plasma concentration time curves at steady-state was 21% more than predicted from the initial single dose. This deviation from linearity was considered to be of minor clinical significance. The kinetics of tenoxicam in elderly were similar to that published for young healthy volunteers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00558254
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