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  • 1
    Electronic Resource
    Electronic Resource
    Human Interindividual Variability in Parameters Related to Health Risks (1999)
    Springer
    Risk analysis 19 (1999), S. 711-726 
    Details
    ISSN: 1539-6924
    Keywords: variability ; exposure ; susceptibility ; risk assessment ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: Abstract This paper reviews existing data on the variability in parameters relevant for health risk analyses. We cover both exposure-related parameters and parameters related to individual susceptibility to toxicity. The toxicity/susceptibility data base under construction is part of a longer term research effort to lay the groundwork for quantitative distributional analyses of non-cancer toxic risks. These data are broken down into a variety of parameter types that encompass different portions of the pathway from external exposure to the production of biological responses. The discrete steps in this pathway, as we now conceive them, are: •Contact Rate (Breathing rates per body weight; fish consumption per body weight) •Uptake or Absorption as a Fraction of Intake or Contact Rate •General Systemic Availability Net of First Pass Elimination and Dilution via Distribution Volume (e.g., initial blood concentration per mg/kg of uptake) •Systemic Elimination (half life or clearance) •Active Site Concentration per Systemic Blood or Plasma Concentration •Physiological Parameter Change per Active Site Concentration (expressed as the dose required to make a given percentage change in different people, or the dose required to achieve some proportion of an individual's maximum response to the drug or toxicant) •Functional Reserve Capacity–Change in Baseline Physiological Parameter Needed to Produce a Biological Response or Pass a Criterion of Abnormal Function Comparison of the amounts of variability observed for the different parameter types suggests that appreciable variability is associated with the final step in the process–differences among people in “functional reserve capacity.” This has the implication that relevant information for estimating effective toxic susceptibility distributions may be gleaned by direct studies of the population distributions of key physiological parameters in people that are not exposed to the environmental and occupational toxicants that are thought to perturb those parameters. This is illustrated with some recent observations of the population distributions of Low Density Lipoprotein Cholesterol from the second and third National Health and Nutrition Examination Surveys.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007045922532
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  • 2
    Electronic Resource
    Electronic Resource
    Evaluation of the Uncertainty in an Oral Reference Dose for Methylmercury Due to Interindividual Variability in Pharmacokinetics (1999)
    Springer
    Risk analysis 19 (1999), S. 547-558 
    Details
    ISSN: 1539-6924
    Keywords: MeHg ; pharmacokinetics ; PBPK model ; variability ; risk assessment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: Abstract An analysis of the uncertainty in guidelines for the ingestion of methylmercury (MeHg) due to human pharmacokinetic variability was conducted using a physiologically based pharmacokinetic (PBPK) model that describes MeHg kinetics in the pregnant human and fetus. Two alternative derivations of an ingestion guideline for MeHg were considered: the U.S. Environmental Protection Agency reference dose (RfD) of 0.1 μg/kg/day derived from studies of an Iraqi grain poisoning episode, and the Agency for Toxic Substances and Disease Registry chronic oral minimal risk level (MRL) of 0.5 μg/kg/day based on studies of a fish-eating population in the Seychelles Islands. Calculation of an ingestion guideline for MeHg from either of these epidemiological studies requires calculation of a dose conversion factor (DCF) relating a hair mercury concentration to a chronic MeHg ingestion rate. To evaluate the uncertainty in this DCF across the population of U.S. women of child-bearing age, Monte Carlo analyses were performed in which distributions for each of the parameters in the PBPK model were randomly sampled 1000 times. The 1st and 5th percentiles of the resulting distribution of DCFs were a factor of 1.8 and 1.5 below the median, respectively. This estimate of variability is consistent with, but somewhat less than, previous analyses performed with empirical, one-compartment pharmacokinetic models. The use of a consistent factor in both guidelines of 1.5 for pharmacokinetic variability in the DCF, and keeping all other aspects of the derivations unchanged, would result in an RfD of 0.2 μg/kg/day and an MRL of 0.3 μg/kg/day.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007017116171
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  • 3
    Electronic Resource
    Electronic Resource
    Pharmacokinetic schedule finding study of the combination of gemcitabine and cisplatin in patients with solid tumors (1999)
    Springer
    Annals of oncology 10 (1999), S. 441-448 
    Details
    ISSN: 1569-8041
    Keywords: cisplatin ; dFdCTP accumulation ; gemcitabine ; pharmacodynamics ; pharmacokinetics ; phase I study ; Pt-DNA adducts
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: To determine possible schedule dependent pharmacokinetic and pharmacodynamic interactions between gemcitabine (2′,2′-difluorodeoxycytidine, dFdC) and cisplatin (cis-diamminedichloroplatinum, CDDP) in patients with advanced stage solid tumors in a phase I trial. Patients and methods: A total of 33 patients with advanced stage solid tumors were treated with gemcitabine (30-min infusion, 800 mg/m2) and cisplatin (one-hour infusion, 50 mg/m2). Sixteen patients had a four-hour interval between gemcitabine (days 1, 8, 15) and cisplatin (days 1 and 8), followed by the reverse schedule and seventeen patients had a 24-hour interval between gemcitabine (days 1, 8, 15) and cisplatin (days 2 and 9), followed by the reverse schedule. Gemcitabine and cisplatin pharmacokinetics were measured in plasma and white blood cells (WBC), isolated from blood samples taken at several time points after the start of treatment. Results: A four-hour time interval between both agents did not reveal major differences in plasma pharmacokinetics of gemcitabine, dFdU (deaminated gemcitabine) and platinum (Pt), and of gemcitabine–triphosphate (dFdCTP) accumulation and Pt-DNA adduct formation in WBC between the two different sequences of gemcitabine and cisplatin. In the patients treated with the 24-hour interval, cisplatin before gemcitabine did not significantly change peak gemcitabine levels and the AUC of plasma dFdU, but tended to increase dFdCTP AUC in WBC 1.5-fold (P 〈 0.06). Gemcitabine before cisplatin decreased the plasma AUC of Pt 2.1-fold (P = 0.03). No significant differences in Pt-DNA adduct levels in WBC were found, although gemcitabine before cisplatin tended to increase the 24-hour retention of Pt-DNA adducts. Creatinine clearance on day 28 was related to the peak plasma levels of total Pt (linear regression coefficient (r) = 0.47, P = 0.02, n = 26). Furthermore, the increase in the Pt-GG to Pt-AG ratio 24 hours after cisplatin treatment was related to the overall response of patients (r = 0.89, P 〈 0.01, n = 8). Conclusions: Of all schedules the treatment of patients with cisplatin 24 hours before gemcitabine led to the highest dFdCTP accumulation in WBC and total Pt levels in plasma. These characteristics formed the basis for further investigation of this schedule in a phase II clinical study.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008301522349
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  • 4
    Electronic Resource
    Electronic Resource
    Sequential administration of temozolomide and fotemustine: Depletion of O6-alkyl guanine-DNA transferase in blood lymphocytes and in tumours (1999)
    Springer
    Annals of oncology 10 (1999), S. 831-838 
    Details
    ISSN: 1569-8041
    Keywords: melanoma ; pharmacodynamics ; pharmacokinetics ; temozolomide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: The DNA repair protein O6-alkylguanine-DNA alkyl transferase (AT) mediates resistance to chloroethylnitrosoureas. Agents depleting AT such as DTIC and its new analogue temozolomide (TMZ) can reverse resistance to chloroethylnitrosoureas. We report the results of a dose finding study of TMZ in association with fotemustine. Patients and methods: Twenty-four patients with metastatic melanoma or recurrent glioma were treated with escalating dose of oral or intravenous TMZ ranging from 300 to 700 mg/m2, divided over two days. Fotemustine 100 mg/m2 was given intravenously on day 2, 4 hours after TMZ. AT depletion was measured in peripheral blood mononuclear cells (PBMCs) and in selected cases in melanoma metastases and was compared to TMZ pharmacokinetics. Results: The maximum tolerated dose (MTD) of TMZ was 400 mg/m2 (200 mg/m2/d) when associated with fotemustine the 2nd day with myelosuppression as dose limiting toxicity. The decrease of AT level in PBMCs was progressive and reached 34% of pretreatment values on day 2. There was however wide interindividual variability. AT reduction was neither dose nor route dependent and did not appear to be related to TMZ systemic exposure (AUC). In the same patients, AT depletion in tumour did not correlate with the decrease of AT observed in PBMCs. Conclusions: PBMCs may not be used as a surrogate of tumour for AT depletion. Further study should concentrate on the pharmacokinetic pharmacodynamic relationship in tumour to provide the basis for individually tailored therapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008304032421
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  • 5
    Electronic Resource
    Electronic Resource
    Pharmacokinetically guided dose escalation of carboplatin in epithelial ovarian cancer: Effect on drug-plasma AUC and peripheral blood drug-DNA adduct levels (1999)
    Springer
    Annals of oncology 10 (1999), S. 329-334 
    Details
    ISSN: 1569-8041
    Keywords: carboplatin ; drug-target interaction ; ovarian cancer ; pharmacokinetically based dosing ; pharmacokinetics ; platinum-DNA adducts
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: Platinum based drugs are active agents in epithelial ovarian cancer and increased platinum drug dose intensity is thought to lead to improved survival, because of the largely untested assumption that increased dose intensity results in an increased interaction of the platinum drug with its target, DNA. In a previously reported phase I trial (Lind et al., J Clin Oncol 1996; 14: 800–5), carboplatin dose intensity was increased by the use of G-CSF to support the bone marrow and using pharmacokinetically-guided carboplatin dosing. The objectives of this study were to validate the carboplatin dosing formula during high dose intensity therapy and evaluate the relationship between systemic carboplatin exposure and Pt-DNA adduct levels in peripheral blood leucocytes. Patients and methods: A total of 17 patients were studied over four levels of dose intensification. The carboplatin dose was calculated using the ‘Calvert formula’. Levels of drug-target interaction in peripheral blood leukocytes were measured using an immunoassay based on a monoclonal antibody that recognises DNA-platinum adducts. Pharmacokinetic measurements were carried out using a previously validated single sample method. Results: The area under the curve of concentration of unbound carboplatin in plasma versus time (AUC) for target AUC values of 5, 7 and 9 mg/ml·min were: 5.6 ± 1.0, 7.3 ± 0.7 and 9.8 ± 0.5 mg/ml·min (mean ± S.D.). There was a good correlation between target and achieved dose intensities (r2 = 0.899) and the slope of the linear regression line was 0.95 (± 0.09 SD) not significantly different to 1.0 (P 〉 0.6). The levels of immunoreactive DNA adducts were not detectable at a target AUC of 5 mg/ml·min but increased progressively at the higher AUC levels. Accumulation of adducts between courses was not detected. Conclusions: Pharmacokinetically-based carboplatin dosing during high intensity therapy accurately predicted the dose required to achieve a target AUC and resulted in consistent patient exposure to active drug. During the dose escalation study, peripheral blood leucocyte DNA platinum-DNA adduct levels were positively related to drug dose and drug AUC.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008355506863
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  • 6
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of interleukin-2 in two anephric patients with metastatic renal cell cancer (1999)
    Springer
    Annals of oncology 10 (1999), S. 1381-1383 
    Details
    ISSN: 1569-8041
    Keywords: (adeno)carcinoma ; interleukin-2 ; kidney neoplasms ; nephrectomy ; pharmacokinetics ; renal cell
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: Most patients with metastatic renal cell carcinoma (RCC) have undergone unilateral- and some bilateral nephrectomy. Because interleukin-2 (IL-2) is thought to be mainly cleared via the kidneys, we investigated whether IL-2 treatment is safe in anephric patients. Patients and methods: The pharmacokinetics of i.v. bolus, i.v. infusion and s.c. recombinant IL-2 were investigated in two anephric patients with progressive metastatic RCC. Results: Following i.v. bolus administration of IL-2, plasma half-lives of 126 and 84 minutes respectively, and plasma clearances of 151 ml/min and 273 ml/min respectively, were measured in the two patients. In one patient plasma clearance of IL-2 was enhanced to 760 ml/min after continuous i.v. infusion of 4 and 6 million IU IL-2/24 hours, as compared to a clearance of 310 ml/min at a dose of 2 million IU IL-2/24 hours. In the other patient, during IL-2 infusion of 2, 4 or 6 × 106 IU/24 hours, each over the course of 3 days, plasma clearance of IL-2 increased from 311 to 761, and to 687 ml/min, respectively. IL-2 could not be detected in haemo- or peritoneal dialysates. Conclusions: IL-2 plasma half-life is only moderately prolonged in anephric patients as compared to patients with normal renal function. Based on our findings, intravenous or subcutaneous treatment of anephric patients with IL-2 seems feasible.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008362620308
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  • 7
    Electronic Resource
    Electronic Resource
    Pharmacokinetic interactions of paclitaxel, docetaxel and their vehicles with doxorubicin (1999)
    Springer
    Annals of oncology 10 (1999), S. 391-395 
    Details
    ISSN: 1569-8041
    Keywords: docetaxel ; doxorubicin ; interaction ; mice ; paclitaxel ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: The combination of doxorubicin (Dx) with paclitaxel or docetaxel is clinically effective but there are concerns regarding the higher incidence of cardiotoxicity of the combination compared with Dx alone. The mechanism of the increased toxicity is still unclear. Purpose: To assess whether there is a pharmacokinetic interaction between paclitaxel, docetaxel or their vehicles and Dx in mice. Materials and methods: CDF1 male mice were treated with Dx either alone (10 mg/kg i.v.) or in combination with paclitaxel (25 mg/kg) or docetaxel (25 mg/kg) or their vehicles, i.e., cremophor-ethanol-glucose (cremophor) or polysorbate80-ethanol-glucose (polysorbate). Four mice were killed 4, 8 or 24 hours after Dx in each experimental group and Dx was assayed in serum and in heart, liver, kidney and spleen by HPLC. Results: Four hours after treatment the concentrations of Dx in heart, liver and kidney were much higher in mice concomitantly treated with paclitaxel, docetaxel (dissolved in either cremophor or polysorbate) and cremophor. At subsequent times the differences were modest and only reached statistical significance in a few cases. Dx metabolites were modified by concomitant treatment with taxanes or their vehicles. In particular, the levels of Dx aglycone in liver and kidney were significantly lower in mice treated with the combination than in mice given Dx alone. Conclusions: paclitaxel, docetaxel and cremophor when given together with Dx modify its distribution and metabolism, increasing Dx levels in many tissues including the heart. This might have some bearing on the toxicity of regimens in which Dx is combined with taxanes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008309916974
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  • 8
    Electronic Resource
    Electronic Resource
    The Metabolism of Atypical Antipsychotic Drugs: An Update (1999)
    Springer
    Annals of clinical psychiatry 11 (1999), S. 145-158 
    Details
    ISSN: 1573-3238
    Keywords: clozapine ; olanzapine ; quetiapine ; risperidone ; sertindole ; ziprasidone ; metabolism ; pharmacokinetics ; flavin-containing monooxygenases ; glucuronidation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This paper reviews the current literature describing the metabolism of both multi-receptor clozapine analogue atypical antipsychotic drugs (clozapine, olanzapine, and quetiapine) and serotonin-dopamine antagonist atypical antipsychotic drugs (risperidone, sertindole and ziprasidone), to highlight the significance of those data in the context of clinical practice. The former group of atypical antipsychotic drugs shares a similar tricyclic structural nucleus and are metabolized through three major categorical metabolic pathways—N +-oxidation, N-glucuronidation, and phases 1 and 2 biotransformation with final glucuronidation before renal excretion. Differing in clozapine and olanzapine, quetiapine has incomplete data describing its metabolism. The latter group of atypical antipsychotic drugs has diversified chemical structures and absence of data on N +-oxidation and N-glucuronidation in the literature. But their metabolic routes in phase 1 biotransformation are versatile although current data are far from completion. No apparent significant drug interactions in clinical practice are reported, although QT prolongation is implicated in all those three drugs. None of all six atypical antipsychotic drugs are identified as significant inhibitors or inducers to any co-administered medication. The author suggests the need for more research to address some pertinent clinical issues in the metabolism of those drugs.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1022312111429
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  • 9
    Electronic Resource
    Electronic Resource
    A human capecitabine excretion balance and pharmacokinetic study after administration of a single oral dose of 14C-labelled drug (1999)
    Springer
    Investigational new drugs 17 (1999), S. 49-56 
    Details
    ISSN: 1573-0646
    Keywords: pharmacokinetics ; capecitabine ; 5-fluorouracil ; phase I trials
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract An excretion balance and pharmacokinetic study was conducted in cancer patients with solid tumors who received a single oral dose of capecitabine of 2000 mg including 50 μ Ci of 14C-radiolabelled capecitabine. Blood, urine and fecal samples were collected until radioactive counts had fallen to below 50 dpm/mL in urine, and levels of intact drug and its metabolites were measured in plasma and urine by LC/MS-MS (mass spectrometry) and 19F-NMR (nuclear magnetic resonance) respectively. Based on the results of the 6 eligible patients enrolled, the dose was almost completely recovered in the urine (mean 95.5%, range 86–104% based on radioactivity measurements) over a period of 7 days after drug administration. Of this, 84% (range 71–95) was recovered in the first 12 hours. Over this time period, 2.64% (0.69–7.0) was collected in the feces. Over a collection period of 24–48h, a total of 84.2% (range 80–95) was recovered in the urine as the sum of the parent drug and measured metabolites (5′-DFCR, 5′-DFUR, 5-FU, FUH2, FUPA, FBAL). Based on the radioactivity measurements of drug-related material, absorption is rapid (tmax 0.25–1.5 hours) followed by a rapid biphasic decline. The parent drug is rapidly converted to 5-FU, which is present in low levels due to the rapid metabolism to FBAL, which has the longest half-life. There is a good correlation between the levels of radioactivity in the plasma and the levels of intact drug and the metabolites, suggesting that these represent the most abundant metabolites of capecitabine. The absorption of capecitabine is rapid and almost complete. The excretion of the intact drug and its metabolites is rapid and almost exclusively in the urine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006263400888
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  • 10
    Electronic Resource
    Electronic Resource
    A Sensitive Docetaxel Assay in Plasma by Solid-Phase Extraction and High Performance Liquid Chromatography – UV Detection: Validation and Suitability in Phase I Clinical Trial Pharmacokinetics (1999)
    Springer
    Investigational new drugs 17 (1999), S. 325-333 
    Details
    ISSN: 1573-0646
    Keywords: docetaxel ; plasma assay ; clinical trials ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract We have developed a specific and sensitive method aiming atdocetaxel (Taxotere®) determination in plasma of treatedpatients. This involved solid-phase extraction of 1 ml of plasmaonto carboxylic acid (CBA) grafted silica cartridges followed byreversed-phase liquid chromatography with UV detection. The bestselectivity was obtained through the use of C18 Uptisphere® asstationary phase. The low limit of quantitation obtained (LOQ:5 ng/ml) allowed measurements of docetaxel up to 24 hours afterone-hour infusions with low dosages of drug (60 mg/m2). Themethod was applied successfully to monitor docetaxel plasma levelswithin two protocols associating fixed dosages of either methotrexate or gemcitabine with escalating doses of Taxotere®.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006327302041
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  • 11
    Electronic Resource
    Electronic Resource
    ACNU, MTX And 5-FU Penetration of Rat Brain Tissue and Tumors (1999)
    Springer
    Journal of neuro-oncology 45 (1999), S. 9-17 
    Details
    ISSN: 1573-7373
    Keywords: ACNU ; MTX ; 5-FU ; pharmacokinetics ; leptomeningeal tumor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The distribution of radio-labeled ACNU, MTX and 5-FU in brain and tumor tissue was studied in female Wistar rats by macroautoradiography after intrathecal administration. In normal rats, ACNU and 5-FU, administered intracisternally, distributed rapidly in the subarachnoid space, ventricular system and cerebrospinal fluid (CSF). 5-FU and MTX penetrated the brain deeply; the diffusional transport of ACNU was limited to a depth of 1 or 2 mm from the CSF surface of the brain. MTX and 5-FU clearance into the blood circulation was rather slow while ACNU cleared relatively quickly. The half time of ACNU, 5-FU and MTX radioactivity at the ventricular surface was 10, 21, and 110 min, respectively, at their maximal concentration after intracisternal administration. In rats with leptomeningeal tumor induced by intracisternal inoculation of Walker 256 cells, the distribution patterns of ACNU, 5-FU, and MTX were essentially the same as in normal rats despite 10–20 cell layers of tumor growing in the subarachnoid space. 5-FU and MTX were able to penetrate tumor masses in the subarachnoid space; MTX penetration was slower than that of 5-FU and ACNU failed to penetrate to more than a depth of 1 or 2 mm from the tumor surface.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006377312403
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  • 12
    Electronic Resource
    Electronic Resource
    Application of a Combined “Effect Compartment/Indirect Response Model” to the Central Nervous System Effects of Tiagabine in the Rat (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 301-323 
    Details
    ISSN: 1573-8744
    Keywords: pharmacokinetics ; pharmacodynamics ; effect compartment model ; indirect response ; sigmoid E max ; tiagabine ; GABA uptake inhibitor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Pharmacological inhibition of GABA uptake transporters provides a mechanism for increasing GABAergic transmission, which may be useful in the treatment of various neurological disorders. The purpose of our investigations was to develop an integrated pharmacokinetic–pharmacodynamic (PK/PD) model for the characterization of the pharmacological effect of tiagabine, R-N-(4,4-di-(3-methylthien-2-yl)but-3-enyl)nipecotic acid, in individual rats in vivo. The tiagabine-induced increase in the amplitude of the EEG 11.5–30 Hz frequency band (β), was used as pharmacodynamic endpoint. Chronically instrumented male Wistar rats were randomly allocated to four groups which received an infusion of 3, 10, or 30 mg kg −1 $$(\bar x \pm SE,{\text{ }}n = 23)$$ $$96 \pm 9$$ ml min -1 kg−1, 1.5ŷ0.1 L kg−1 and 20ŷ0.2 min.A time delay was observed between the occurrence of maximum plasma drug concentrations and maximal response. A physiological PK/PD model has been used to account for this time delay, in which a biophase was postulated to account for tiagabine available to the GABA uptake carriers in the synaptic cleft and the increase in EEG effect was considered an indirect response due to inhibition of GABA uptake carriers. The population values for the pharmacodynamic parameters characterizing the delay in pharmacological response relative to plasma concentrations were keo=0.030 min −1 and kout=81 min−1, respectively. Because of the large difference in these values the PK/PD model was simplified to the effect compartment model. Population estimates $$(\bar x \pm SE)$$ were E0=155 ŷ 6 μV, Emax=100 ŷ 5 μV, EC50=287 ŷ 7 ng ml−1, Hill factor=1.8 ŷ 0.2 and keo=0.030 ŷ 0.002 min −1. The results of this analysis show that for tiagabine the combined “effect compartment-indirect response” model can be simplified to the classical “effect compartment” model.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1020999114109
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  • 13
    Electronic Resource
    Electronic Resource
    Assuming Peripheral Elimination: Its Impact on the Estimation of Pharmacokinetic Parameters of Muscle Relaxants (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 491-512 
    Details
    ISSN: 1573-8744
    Keywords: muscle relaxants ; peripheral elimination ; pharmacokinetics ; peripheral concentrations ; volume of distribution ; pharmacokinetic model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract For anesthetic drugs undergoing nonorgan-based elimination, there is a definite trend towards using pharmacokinetic (PK) models in which elimination can occur from both central (k10 ) and peripheral compartments(k20 ). As the latter cannot be assessed directly, assumptions have to be made regarding its value. The primary purpose of this paper is to evaluate the impact of assuming various degrees of peripheral elimination on the estimation of PK parameters. For doing so, an explanatory model is presented where previously published data from our laboratory on three muscle relaxants, i.e., atracurium, doxacurium, and mivacurium, are used for simulations. The mathematical aspects for this explanatory model as well as for two specific applications are detailed. Our simulations show that muscle relaxants having a short elimination half-life are more affected by the presence of peripheral elimination as their distribution phase occupies the major proportion of their total area under the curve. Changes in the exit site dependent PK parameters (Vdss ) are also mostly significant when k20 is smaller than k10 . Although the physiological processes that determine drug distribution and those affecting peripheral elimination are independent, the two are mathematically tied together in the two-compartment model with both central and peripheral elimination. It follows that, as greater importance is given to k20 , the rate of transfer from the central compartment (k12 ) increases. However, as a result of a proportional increase in the volume of the peripheral compartment, peripheral concentrations remain unchanged whether or not peripheral elimination is assumed. These findings point out the limitations of compartmental analysis when peripheral elimination cannot be measured directly.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1023286329945
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  • 14
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and Dosage Regimen of Enrofloxacin in Buffalo Bulls after Intramuscular Administration (1999)
    Springer
    Veterinary research communications 23 (1999), S. 501-505 
    Details
    ISSN: 1573-7446
    Keywords: antibiotics ; buffalo ; disposition ; dosage ; enrofloxacin ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The disposition kinetics and dosage regimen of enrofloxacin were investigated in breeding buffalo bulls following a single intramuscular administration of 5 mg/kg. The absorption half-life, half-life of the terminal phase, apparent volume of distribution and total body clearance were 0.262±0.099 h, 1.97±0.23 h, 0.61±0.13 L/kg and 210.2±18.6 ml/(kg.h), respectively. Therapeutic plasma levels (≥1 μg/ml) were maintained for up to 6 h. A satisfactory intramuscular dosage regimen for enrofloxacin in buffalo bulls would be 8.5 mg/kg followed by 8.0 mg/kg at 8 h intervals.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006366507016
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  • 15
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of Amoxicillin Trihydrate in Desert Sheep and Nubian Goats (1999)
    Springer
    Veterinary research communications 23 (1999), S. 507-514 
    Details
    ISSN: 1573-7446
    Keywords: amoxicillin ; bioavailability ; breed ; goats ; pharmacokinetics ; sheep
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The pharmacokinetics of amoxicillin were studied in five Desert sheep and five Nubian goats after intravenous (i.v.) or intramuscular (i.m.) administration of a single dose of 10 mg/kg body weight. Following i.v. injection, the plasma concentration-versus-time data were best described by a two-compartment open model. The kinetic variables were similar in both species except for the volume of the central compartment (Vc), which was larger in sheep (p〈0.05). Following i.m. injection, except for the longer half-life time of absorption in goats (p〈0.05), there were no significant differences in other pharmacokinetic parameters between sheep and goats. The route of amoxicillin administration had no significant effect on the terminal elimination half-life in either species. The bioavailability of the drug (F) after i.m. administration was high (〉0.90) in both species. These results indicate that the pharmacokinetics of amoxicillin did not differ between sheep and goats; furthermore, because of the high availability and short half-life of absorption, the i.m. route gives similar results to the i.v. route. Therefore, identical intramuscular and intravenous dose regimens should be applicable to both species.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006318623854
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  • 16
    Electronic Resource
    Electronic Resource
    Comparative Anthelmintic Activity of Strategic Sustained Low-level Administration of Albendazole in Feed Pellets Compared to Single Doses of Closantel and Tetramisole against Natural Ovine Parasitic Gastroenteritis (1999)
    Springer
    Tropical animal health and production 31 (1999), S. 193-204 
    Details
    ISSN: 1573-7438
    Keywords: albendazole ; anthelmintic ; closantel ; control ; delivery ; dosage ; Haemonchus contortus ; in-feed ; pharmacokinetics ; sheep ; tetramisole
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The strategic use of single therapeutic doses of closantel, tetramisole or sustained low-level administration of albendazole in feed pellets in controlling naturally acquired parasitic gastroenteritis in sheep was investigated on a farm in semi-arid Rajasthan, India. A total of 303 5- to 6-month-old sheep were divided into three groups. Two groups were dosed with single therapeutic doses of closantel and tetramisole and the third group was given a low-level medication with albendazole through feed pellets for 30 days. Faecal egg counts revealed significantly lower counts (p〈0.001) in the group treated with closantel compared to the other two groups. The faecal egg counts in the group receiving sustained low-level albendazole rose after withdrawal of the medication but remained significantly lower than those in the group treated with tetramisole up to 7 weeks after treatment (p〈0.05). On the other hand, in the group treated with tetramisole, the mean faecal egg count rose from 3 weeks after treatment and remained continuously higher than those in any other group up to 12 weeks after treatment. The closantel-treated group gained more body weight but the first six-monthly greasy fleece yield was greater in the group treated with medicated pellets. During the first 3 months of the experiment, three animals in the group treated with tetramisole died of parasitic gastroenteritis. Following sustained low-level administration of albendazole in feed pellets, the plasma disposition curve of both the sulphoxide and sulphone metabolites reached its plateau level by day 5 and remained almost constant thereafter. The comparative cost-effectiveness of the three treatment regimes during the first 3 months of treatment was best for the group treated with closantel followed by the group treated with medicated feed pellets.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005223025851
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  • 17
    Electronic Resource
    Electronic Resource
    Some Pharmacokinetic Parameters of Eprinomectin in Goats following Pour-on Administration (1999)
    Springer
    Veterinary research communications 23 (1999), S. 449-455 
    Details
    ISSN: 1573-7446
    Keywords: eprinomectin ; goat ; pharmacokinetics ; topical application
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Some pharmacokinetic parameters of eprinomectin were determined in goats following topical application at a dose rate of 0.5 mg/kg. The plasma concentration versus time data for the drug were analysed using a one-compartment model. The maximum plasma concentration of 5.60±1.01 ng/ml occurred 2.55 days after administration. The area under the concentration–time curve (AUC) was 72.31±11.15 ng day/ml and the mean residence time (MRT) was 9.42±0.43 days. Thus, the systemic availability of eprinomectin to goats was significantly lower than that for cows. The low concentration of eprinomectin in the plasma of goats suggests that the pour-on dose of 0.5 mg/kg would be less effective in this species than in cows. Further relevant information about the optimal dosage and residues in the milk of dairy goats is needed before eprinomectin should be used in this species.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006373609314
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  • 18
    Electronic Resource
    Electronic Resource
    Lack of Sex-influence on the In Vitro Metabolism of Ivermectin by Hepatic Microsomal Preparations from Cattle (1999)
    Springer
    Veterinary research communications 23 (1999), S. 223-227 
    Details
    ISSN: 1573-7446
    Keywords: cattle ; gender ; ivermectin ; metabolism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006249009553
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  • 19
    Electronic Resource
    Electronic Resource
    Influence of Diet Type and Pretreatment Fasting on the Disposition Kinetics of Albendazole in Sheep (1999)
    Springer
    Veterinary research communications 23 (1999), S. 229-240 
    Details
    ISSN: 1573-7446
    Keywords: albendazole ; diet ; fasting ; green fodder ; pharmacokinetics ; sheep
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The influence of the quality and quantity of diets on the disposition kinetics of albendazole were studied in sheep in two different experiments. The plasma concentration profiles of albendazole sulphoxide and albendazole sulphone were measured following intraruminal administration of albendazole at 5.0 mg/kg body weight in weaner sheep offered three different diets: 100% green Sorghum spp., 100% dry mature Cenchrus ciliaris hay and a 50:50 mix of these two diets. The peak plasma concentrations and the availability of the albendazole metabolites, as measured by the area under the concentration–time curve, were significantly higher (p〈0.01) in the animals offered exclusively dry fodder compared to other diets. Changing the diet from dry to green fodder resulted in a significantly lower systemic availability of the drug metabolites. It is suggested that a decreased transit time of the digesta in the bowel on the green diet, with its high water content, limited the systemic availability of the drug by reducing the time available for gastrointestinal absorption. An experiment on the influence of different levels of pretreatment fasting on the pharmacokinetics of albendazole revealed significantly higher (p〈0.05) plasma concentrations of the anthelmintically active sulphoxide metabolite from 12 h onwards following administration of the drug in animals subjected to 24 h of pretreatment fasting compared to other groups with pretreatment fasting of 8, 12 or 18 h. The area under the concentration–time curve and the minimum residence time of the drug metabolites were significantly greater (p〈0.05) in animals that had been fasted for 24 h. It is suggested that fasting induces a decrease in the flow of digesta through the gastrointestinal tract of ruminants and prolongs the duration of dissolution of the drug, resulting in enhancement of the absorption of albendazole and of the systemic availability of its metabolites.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006201226391
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  • 20
    Electronic Resource
    Electronic Resource
    Rapid Attainment of Steady-State Plasma Drug Concentrations Within Precise Limits in Multicompartment Mammillary Systems (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 325-328 
    Details
    ISSN: 1573-8744
    Keywords: anesthetic techniques ; continuous infusion ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract We have previously described a method of rapidly obtaining a specified steady-state plasma concentration of an intravenous drug within precise limits. However the method is limited to drugs whose disposition may be characterized by an open two-compartment system. In this paper, we illustrate how the method can be extended to drugs whose disposition may be characterized by a mammillary model with any number of compartments. Refinements of our previous technique are also described.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1020951230947
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  • 21
    Electronic Resource
    Electronic Resource
    Population Pharmacokinetics and Pharmacodynamics of the Anti-CD11a Antibody hu1124 in Human Subjects with Psoriasis (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 397-420 
    Details
    ISSN: 1573-8744
    Keywords: psoriasis ; hu1124 ; CD11a ; CD3-positive lymphocytes ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of hu1124, a human anti-CD11a antibody, were investigated in human subjects with psoriasis. CD11a is a subunit of LFA-1, a cell surface molecule involved in T cell mediated immune responses. Subjects received a single dose of 0.03, 0.1, 0.3, 0.6, 1, 2, 3, or 10 mg/kg of hu1124 intravenously over 1–3 hr. Blood samples were collected at selected times from 60 min to 72 days after administration. Plasma samples were assayed for hu1124 by ELISA, and pharmacokinetic analyses were performed on the drug plasma concentrations. As the dose of hu1124 was increased, the clearance decreased from 322 ml/day per kg at 0.1 mg/kg to 6.6 ml/day per kg at 10 mg/kg of hu1124. The plasma hu1124 concentration–time profile suggested that the clearance of hu1124 was saturable above 10 μg/ml. In addition, treatment with hu1124 caused a rapid reduction in the level of CD11a expression on CD3-positive lymphocytes (T cells) to about 25% of pretreatment levels. Regardless of the hu1124 dose administered, cell surface CD11a remained at this reduced level as long as hu1124 was detectable (〉0.025 μg/ml) in the plasma. When hu1124 levels fell below 3 μg/ml, the drug was rapidly cleared from the circulation and expression of CD11a returned to normal within 7–10 days thereafter. In vitro, half-maximal binding of hu1124 to lymphocytes was achieved at about 0.1 μg/ml and saturation required more than 10 μg/ml. One of the receptor-mediated pharmacokinetic/pharmacodynamic models which was developed describes the dynamic interaction of hu1124 binding to CD11a, resulting in the removal of hu1124 from the circulation and reduction of cell surface CD11a. The model accounts for the continually changing number of CD11a molecules available for removing hu1124 from the circulation based on prior exposure of cells expressing CD11a to hu1124. In addition, the model also accounts for saturation of CD11a molecules by hu1124 at drug concentrations of approximately 10 μg/ml, thereby reducing the clearance rate of hu1124 with increasing dose.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1020917122093
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  • 22
    Electronic Resource
    Electronic Resource
    Drug–Drug Pharmacodynamic Interaction Detection by a Nonparametric Population Approach. Influence of Design and of Interindividual Variability (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 531-554 
    Details
    ISSN: 1573-8744
    Keywords: drug–drug interactions ; NPML ; experimental design ; pharmacodynamic variability ; pharmacokinetics ; entropy ; covariate ; second stage model ; controlled trial
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Population approaches are appealing methods for detecting then assessing drug–drug interactions mainly because they can cope with sparse data and quantify the interindividual pharmacokinetic (PK) and pharmacodynamic (PD) variability. Unfortunately these methods sometime fail to detect interactions expected on biochemical and/or pharmacological basis and the reasons of these false negatives are somewhat unclear. The aim of this paper is firstly to propose a strategy to detect and assess PD drug–drug interactions when performing the analysis with a nonparametric population approach, then to evaluate the influence of some design variates (i.e., number of subjects, individual measurements) and of the PD interindividual variability level on the performances of the suggested strategy. Two interacting drugs A and B are considered, the drug B being supposed to exhibit by itself a pharmacological action of no interest in this work but increasing the A effect. Concentrations of A and B after concomitant administration are simulated as well as the effect under various combinations of design variates and PD variability levels in the context of a controlled trial. Replications of simulated data are then analyzed by the NPML method, the concentration of the drug B being included as a covariate. In a first step, no model relating the latter to each PD parameter is specified and the NPML results are then proceeded graphically, and also by examining the expected reductions of variance and entropy of the estimated PD parameter distribution provided by the covariate. In a further step, a simple second stage model suggested by the graphic approach is introduced, the fixed effect and its associated variance are estimated and a statistical test is then performed to compare this fixed effect to a given value. The performances of our strategy are also compared to those of a non-population-based approach method commonly used for detecting interactions. Our results illustrate the relevance of our strategy in a case where the concentration of one of the two drugs can be included as a covariate and show that an existing interaction can be detected more often than with a usual approach. The prominent role of the interindividual PD variability level and of the two controlled factors is also shown.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1023290530853
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  • 23
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and Hemostatic Effects of Saruplase in Patients with Acute Myocardial Infarction: Comparison of Infusion, Single-Bolus, and Split-Bolus Administration (1999)
    Springer
    Journal of thrombosis and thrombolysis 8 (1999), S. 213-221 
    Details
    ISSN: 1573-742X
    Keywords: saruplase ; pharmacokinetics ; bolus administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Saruplase, or unglycosylated, single-chain urokinase-type plasminogen activator (scu-PA) selectively activates fibrin-bound plasminogen, and is subsequently converted to its two-chain derivative tcu-PA (urokinase) by plasmin. The efficacy of a 20 mg IV bolus followed by an infusion of 60 mg over 1 hour (standard regimen) has been demonstrated in acute myocardial infarction (AMI). The Bolus Administration of Saruplase in Europe (BASE) study compared the efficacy of standard therapy, single bolus (80 mg), and split bolus (2 × 40 mg at 30-minute intervals) in AMI. In a substudy of BASE, the pharmacokinetics of total u-PA activity (amidolytic activity after plasmin treatment), high molecular weight (HMW) u-PA antigen, and tcu-PA activity were compared in patients receiving standard therapy (n = 4), single bolus (n = 4), or split bolus (n = 5). Total u-PA activity and HMW u-PA antigen were similar. The maximum concentration (Cmax,, mean ± SD) of total u-PA activity was 2.2 ± 0.3 µg/mL after standard therapy, 16.3 ± 3.9 µg/mL after single bolus, and 8.2 ± 1.6 ug/mL after split bolus. The area under the concentration versus time curve (AUC) values of total u-PA activity were 1.7 ± 0.1 µg/mL*h (standard therapy), 4.0 ± 0.9 µg/mL*h (bolus), and 3.0 ± 0.7 µg/mL*h (split bolus). The dominant initial half-lives (t1/2 α) were 7.1 ± 1.1 minutes (standard), 8.8 ± 0.8 minutes (bolus), and 5.1 ± 2.1 minutes (split bolus). Maximum plasma concentrations of of tcu-PA activity were observed at 5.2 ± 7 minutes (standard), 21 ± 10 minutes (bolus), and 42 ± 2 minutes (split bolus). Cmax was lowest after standard therapy (0.6 ± 0.3 µg/mL), highest after bolus (4.2 ± 2.2 µg/mL), and approximately twice as high as standard therapy after split bolus (1.3 ± 0.8 µg/mL). After standard therapy the mean fibrinogen concentration decreased gradually from approximately 300 mg/dL to 70 mg/dL at 90 and 120 minutes. After a single bolus the fibrinogen concentration decreased below the limit of quantification within 30 minutes and remained there for at least 120 minutes. Directly after the second 40 mg dose of the split bolus, the fibrinogen levels had an accelerated and more pronounced decrease to approximately 65 mg/dL at 90 and 120 minutes. A single bolus results in very high early total u-PA activity, which accelerates the appearance of tcu-PA activity and fibrinogen consumption. The pharmacokinetics and hemostatic effects of the split-bolus regimen are more comparable with those of standard therapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008914321384
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  • 24
    Electronic Resource
    Electronic Resource
    A Compartmental Analysis of the Pharmacokinetics of Propofol in Sheep (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 329-338 
    Details
    ISSN: 1573-8744
    Keywords: propofol ; anaesthesia ; pharmacokinetics ; compartment models ; effect compartment models
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Conventional compartmental pharmacokinetic analysis may provide inaccurate prediction of drug concentrations after rapid iv administration. To examine this, compartment and effect compartment analysis was applied to measured arterial and brain concentrations of propofol in sheep after iv administration at a range of doses and dose rates. Although arterial and brain concentrations were reasonably well fitted to compartmental and effect compartment models for individual doses and dose rates, the structure and parameters of all models differed with changes in both dose and rate of administration. There were large discrepancies between predicted and measured arterial and brain concentrations when these models were used to predict drug concentrations across doses and dose rates. These data support the limitations of this type of modeling in the setting of rapid propofol administration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1020903315017
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  • 25
    Electronic Resource
    Electronic Resource
    Indirect-Response Modeling of Desmopressin at Different Levels of Hydration (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 513-529 
    Details
    ISSN: 1573-8744
    Keywords: desmopressin ; indirect-response modeling ; overhydration ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The objective of the present study was to investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of desmopressin in healthy male subjects at different levels of overhydration. Also, we examined if an indirect-response model could be related to renal physiology and the pharmacological action of desmopressin. Eight healthy male subjects participated in this open, randomized crossover study with three periods. Each subject was orally water loaded (0 to 20ml·kg −1 body weight) on 3 study days in order to achieve three different levels of hydration. After the initial water load, urine was voided every 15 min and the volumes were measured. To ensure continuous overhydration the subjects replaced their fluid loss with drinking-water. When a steady-state diuresis was achieved after approximately 2 hr, 0.396 μg of desmopressin was administered intravenously as a bolus injection. Blood was sampled and urine was collected at intervals throughout the study day (10 hr). An indirect-response model, where desmopressin was assumed to inhibit the elimination of response, was fit to the urine osmolarity data. There were no statistically significant effects of different levels of hydration, as expressed by urine flow rate at baseline, on the estimates of the PK and PD model parameters. The calculated terminal half-lives of elimination (t1/2 β) ranged between 2.76 and 8.37 hr with an overall mean of 4.36 hr. The overall means of plasma clearance and the volumes of distribution of the central compartment (Vc ) and at steady state (Vss ) were estimated to be 1.34 (SD 0.35) ml·min −1 ·kg −1 , 151 (SD28) ml·kg −1 , and 386 (SD 63) ml·kg −1 , respectively. High urine flow rate, indicating overhydration, produced a diluted urine and thus a low osmolarity at baseline (R0 ). The effect of the urine flow rate on the urine osmolarity at baseline was highly significant (p〈0.0001). The mean values for IC50 and the sigmoidicity factor (γ) were 3.7 (SD 1.2) pg·ml −1 and 13.0 (SD 3.5), respectively. In most cases when there was a high urine flow rate at baseline, the model and the estimated PD parameters could be related to the pharmacological action of desmopressin and renal physiology. Thus, the indirect-response model used in this study offers a mechanistic approach of modeling the effect of desmopressin in overhydrated subjects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1023238514015
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  • 26
    Electronic Resource
    Electronic Resource
    Constructing a Prediction Interval for Time to Reach a Threshold Concentration Based on a Population Pharmacokinetic Analysis: An Application to Basiliximab in Renal Transplantation (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 213-230 
    Details
    ISSN: 1573-8744
    Keywords: prediction interval ; pharmacokinetics ; population analysis ; NONMEM ; inverse regression ; immunosuppressives
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Basiliximab is an immunosuppressant chimeric monoclonal antibody directed to the human interleukin-2 receptor α-chain used for prevention of acute rejection episodes in organ transplantation. The minimally effective serum concentration necessary to saturate receptor epitopes in kidney transplant patients is 0.2 μg/ml. To guide dose selection for Phase 3 efficacy trials, a population pharmacostatistical model was fitted to intensively sampled Phase 2 pharmacokinetic data. This served as a basis from which to examine candidate dose regimens with respect to the duration over which receptor-saturating concentrations would be achieved posttransplant. Three prediction methods were assessed: one based on simulations, and two others based on first-order approximation using either inverse regression or inversion of confidence intervals. An 80% prediction interval was generated by each method to evaluate its predictive performance against prospectively collected Phase 3 data in 39 renal transplant patients who received two injections of 20mg basiliximab, one prior to surgery and one on Day 4 posttransplant. All methods provided correct prediction of the duration of receptor-saturating concentration. As anticipated, the best performance was obtained from the simulation method which predicted 30 values in the 80% prediction interval, 19.7–52.7 days. The actually observed 80% interval from the Phase 3 data was 23.7–58.3 days.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1020658023774
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  • 27
    Electronic Resource
    Electronic Resource
    Modeling Interactions between Adrenal Suppression and T-Helper Lymphocyte Trafficking during Multiple Dosing of Methylprednisolone (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 559-575 
    Details
    ISSN: 1573-8744
    Keywords: T-helper cells ; trafficking ; rebound ; corticosteroids ; circadian rhythm ; methylprednisolone ; drug interactions ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A physiologic pharmacodynamic model was developed to jointly characterize the effects of corticosteroid treatment on adrenal suppression and T-helper cell trafficking during single and multiple dosing in asthmatic patients. Methylprednisolone (MP), cortisol, and T-helper cell concentrations obtained from a previously published study during single day and 6 days of multiple dosing MP treatment were examined. The formation and disposition kinetics of MP were described with a compartmental model. The biorhythmic profile of basal cortisol secretion rate was analyzed using a recent Fourier approach based on circadian harmonics. A three-compartment loop model was proposed to represent three major T-helper cell pools: blood, extravascular site, and lymph nodes. T-helper cell synthesis and degradation rate constants were obtained from the literature. The suppressive effects of cortisol and MP on T-helper cell concentrations were described with a joint additive inhibition function altering the cell migration rate from lymph nodes to blood. The model adequately described both plasma cortisol profiles and T-helper cells in blood after single and multiple doses of MP. The potency of MP for suppression of cortisol secretion was estimated as IC50 = 0.8 ng/ml. The biorhythmic nature of the basal T-helper cells in blood was well described as under the influence of basal circadian cortisol concentrations with IC50 = 79 ng/ml. The model fitted potency of MP for suppression of T-helper cells was IC50 = 4.6 ng/ml. The observed rebound of T-helper cells in blood can also be described by the proposed model. The rhythm and suppression of plasma cortisol and T-helper cells before and during single and multiple dose MP treatment were adequately described by these extended indirect response models.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1020974408657
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  • 28
    Electronic Resource
    Electronic Resource
    Relationship Between Etomidate Plasma Concentration and EEG Effect in the Rat (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 924-929 
    Details
    ISSN: 1573-904X
    Keywords: etomidate ; pharmacokinetics ; pharmacodynamics ; rat ; electroencephalogram
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The effect-plasma concentration relationship of etomidate was studied in the rat using electroencephalographic changes as a pharmacodynamic parameter. Methods. Etomidate was infused (50 mg/kg/h) in chronically instrumented rats (n = 6) until isoelectric periods of 5 s or longer were observed in the electroencephalogram (EEG). The EEG was continuously recorded during the experiment and frequent arterial blood samples were taken for determination of etomidate plasma concentrations. The changes observed in the raw EEG signal were quantified using aperiodic analysis in the 2.5−7.5 Hz frequency band. The return of the righting reflex was used as another parameter of anesthesia. Results. A mean dose of 8.58 ± 0.41 mg/kg needed to be infused to reach the end point of 5 s isoelectric EEG. The plasma concentration time profiles were most adequately fitted using a three-exponential model. Systemic clearance, volume of distribution at steady-state and elimination half-life averaged 93 ± 6 ml/min/kg, 4.03 ± 0.24 l/kg and 59.4 ± 10.7 min respectively. The EEG effect-plasma concentration relationship was biphasic exhibiting profound hysteresis. Semi-parametric minimization of this hysteresis revealed an equilibration half-life of 2.65 ± 0.15 min, and the biphasic effect-concentration relationship was characterized nonparametrically by descriptors. The effect-site concentration at the return of the righting reflex was 0.44 ± 0.03 μg/ml. Conclusions. The results of the present study show that the concentration-effect relationship of etomidate can be characterized in individual rats using aperiodic analysis in the 2.5−7.5 Hz frequency band of the EEG. This characterization can be very useful for studying the influence of diseases on the pharmacodynamics of etomidate in vivo.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018894523734
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  • 29
    Electronic Resource
    Electronic Resource
    Prediction of Pharmacokinetic Parameters and the Assessment of Their Variability in Bioequivalence Studies by Artificial Neural Networks (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 944-948 
    Details
    ISSN: 1573-904X
    Keywords: bioequivalence ; neural networks ; prediction ; pharmacokinetics ; verapamil
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The methodology of predicting the pharmacokinetic parameters (AUC, cmax, tmax) and the assessment of their variability in bioequivalence studies has been developed with the use of artificial neural networks. Methods. The data sets included results of 3 distinct bioequivalence studies of oral verapamil products, involving a total of 98 subjects and 312 drug applications. The modeling process involved building feedforward/backpropagation neural networks. Models for pharmacokinetic parameter prediction were also used for the assessment of their variability and for detecting the most influential variables for selected pharmacokinetic parameters. Variables of input neurons based on logistic parameters of the bioequivalence study, clinical-biochemical parameters, and the physical examination of individuals. Results. The average absolute prediction errors of the neural networks for AUC, cmax, and tmax prediction were: 30.54%, 39.56% and 30.74%, respectively. A sensitivity analysis demonstrated that for verapamil the three most influential variables assigned to input neurons were: total protein concentration, aspartate aminotransferase (AST) levels, and heart-rate for AUC, AST levels, total proteins and alanine aminotransferase (ALT) levels, for cmax, and the presence of food, blood pressure, and body-frame for tmax. Conclusions. The developed methodology could supply inclusion or exclusion criteria for subjects to be included in bioequivalence studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018857108713
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  • 30
    Electronic Resource
    Electronic Resource
    A Physiological Pharmacokinetic Model for Solute Disposition in Tissues Below a Topical Application Site (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1392-1398 
    Details
    ISSN: 1573-904X
    Keywords: topical application ; dermal absorption ; cutaneous perfusion ; pharmacokinetics ; binding ; half life
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Many compounds are applied to the skin with the aim of targeting deeper underlying tissues. This work sought to define the pharmacokinetics of solutes in tissues below a topical application site in terms of perfusate binding, tissue binding and perfusate flow rate. Methods. The disposition kinetics of diclofenac in a single pass perfused limb preparation after dermal application disposition was studied using dextran and bovine serum albumin (BSA) containing perfusates. A pharmacokinetic model was then developed to relate the tissue retention half lives for diclofenac, diazepam, water, lignocaine and salicylate to their fraction unbound in the tissues, their fraction unbound in the perfusate and the perfusate flow rate. Results. Diclofenac had estimated tissue retention half lives of 18.1 hr and 3.5 hr for the dextran and BSA containing perfusates, respectively. The fraction of diclofenac and other solutes unbound in the tissues correlated with their corresponding fraction unbound in the perfusate. The tissue retention half lives for diclofenac and other solutes could be described in terms of the fraction of solute unbound in the tissues and perfusate, together with the flow rate. Conclusions. The tissue pharmacokinetics of solutes below a topical application are a function of their binding in the tissues, binding in perfusate and local blood flow.
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    URL: http://dx.doi.org/10.1023/A:1018998908655
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    Venous Irritation, Pharmacokinetics, and Tissue Distribution of Tirilazad in Rats Following Intravenous Administration of a Novel Supersaturated Submicron Lipid Emulsion (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 930-938 
    Details
    ISSN: 1573-904X
    Keywords: submicron lipid emulsion ; supersaturation ; tirilazad ; venous irritation ; pharmacokinetics ; tissue distribution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To compare the venous irritation, pharmacokinetics, and tissue distribution of tirilazad in rats after intravenous administration of a submicron lipid emulsion with that of an aqueous solution. Methods. Venous irritation was determined by microscopic evaluation of injury to the lateral tail veins of rats. Pharmacokinetic parameters were determined by following plasma concentrations of drug. Tissue distribution of [14C]-tirilazad was determined by quantitative whole body autoradiography. Results. Single dose injections of tirilazad as an emulsion at doses ranging from 1.52 mg to 13.5 mg were non-irritating whereas the solution was irritating at a dose of 1.3 mg. The pharmacokinetic parameters were not statistically different between the emulsion and the solution (p 〉 0.2) at doses of 6 mg/kg/day and 20 mg/kg/day. However, at 65 mg/kg/day dose, a higher AUC(0,6) (4-fold) and lower Vss (18-fold) and CL(5-fold) were observed for the lipid emulsion as compared to the solution (p 〈 0.05). Tissue distribution showed higher initial concentrations (two fold or more) in most tissues for the solution. These values, however, equilibrated by 4 h and AUC(0,4) differences were less than two fold in most tissues. Conclusions. Formulating tirilazad in the lipid emulsion significantly reduces the venous irritation without changing the pharmacokinetics and tissue distribution at low doses.
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    URL: http://dx.doi.org/10.1023/A:1018846607804
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  • 32
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    Electronic Resource
    Distribution and Binding Kinetics of Ciprofloxacin and Ofloxacin in the Hindlimb of the Rat (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 587-591 
    Details
    ISSN: 1573-904X
    Keywords: quinolones ; pharmacokinetics ; permeability ; tissue binding ; hindlimb
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011939616948
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  • 33
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    Electronic Resource
    Pharmacokinetics of Methotrexate in the Extracellular Fluid of Brain C6-Glioma After Intravenous Infusion in Rats (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1219-1225 
    Details
    ISSN: 1573-904X
    Keywords: C6-glioma ; methotrexate ; microdialysis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Establishment of the pharmacokinetic profile of methotrexate (MTX) in the extracellular fluid (ECF) of a brain C6-glioma in rats. Methods. Serial collection of plasma samples and ECF dialysates after i.v. infusion of MTX (50 or 100 mg/kg) for 4 h. HPLC assay. Results. Histological studies revealed the presence of inflammation, edema, necrosis, and hemorrhage in most animals. In vivo recovery (reverse dialysis) was 10.8 ± 5.3%. MTX concentrations in tumor ECF represented about 1−2% of the plasma concentrations. Rapid equilibration between MTX levels in brain tumor ECF and plasma. ECF concentrations almost reached steady-state by the end of the infusion (4 h), then decayed in parallel with those in plasma. Doubling of the dose did not modify MTX pharmacokinetic parameters (t1/2α, t1/2β, MRT, fb, Vd, and CLT), except for a 1.7-fold increase of AUCPlasma and a 3.8-fold increase in AUCECF which resulted in a 2.3-fold increase in penetration (AUCECF/AUCPlasma). In spite of an important interindividual variability, a relationship between MTX concentrations in plasma and tumor ECF could be established from mean pharmacokinetic parameters. Conclusions. High plasma concentrations promote the penetration of MTX into brain tissue. However, free MTX concentrations in tumor ECF remain difficult to predict consistently.
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    URL: http://dx.doi.org/10.1023/A:1018945529611
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  • 34
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    Electronic Resource
    Evaluation of the Pharmacokinetic Features and Tissue Distribution of the Potent Nonnucleoside Inhibitor of HIV-1 Reverse Transcriptase, N-[2-(2-fluorophenethyl)]-N′-[2-(5-bromopyridyl)]-thiourea (HI-240) with an Analytical HPLC Method (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1226-1232 
    Details
    ISSN: 1573-904X
    Keywords: HI-240 ; nonnucleoside inhibitor ; pharmacokinetics ; HPLC
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The purpose of the present study was to examine the pharmacokinetic features and tissue distribution of N-[2-(2-fluorophenethyl)]-N′-[2-(5-bromopyridyl)]-thiourea (HI-240), a novel non-nucleoside inhibitor of HIV reverse transcriptase with potent anti-viral activity against AZT-sensitive as well as multidrug-resistant HIV-1 strains. Methods. A sensitive and accurate high performance liquid chromatography (HPLC)-based quantitative detection method was established to measure concentrations of HI-240 in pharmacokinetic studies. The plasma concentration-time data were modeled by using the WinNonlin program to estimate the pharmacokinetic parameter values. Results. HI-240 had an elimination half-life of 78.3 ± 2.0 min after i.v. administration and 196.8 ± 3.1 min after i.p. administration. The systemic clearance of HI-240 was 2194 ± 61 ml/h/kg after i.v. administration and 9339 ± 1160 ml/h/kg after i.p. administration. Following i.v. injection, HI-240 rapidly distributed to and accumulated in multiple tissues with particularly high accumulation in adipose tissue, adrenal gland, and uterus+ovary. The concentration of HI-240 in brain tissue was comparable to that in the plasma, indicating that HI-240 easily crosses the blood-brain-barrier. Following i.p. injection, HI-240 was rapidly absorbed with a t1/2ka and a tmax values of less than 10 min. Following oral administration, HI-240 was absorbed with a t1/2ka of 4.2 ±1.1 min and a tmax of 95.1 ± 25.1 min. The intraperitoneal bioavailability was estimated at 23.5%, while the oral bioavailability was only 1%. Conclusions. The HPLC-based accurate and precise analytical detection method and pilot pharmacokinetic studies described herein provide the basis for advanced preclinical pharmacodynamic studies of HI-240. The ability of HI-240 to distribute rapidly and extensively into extravascular compartments and easily cross the blood-brain barrier represent significant pharmacokinetic advantages over AZT.
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    URL: http://dx.doi.org/10.1023/A:1014814313681
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  • 35
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    Electronic Resource
    Pharmacokinetic Features and Metabolism of Calphostin C, A Naturally Occurring Perylenequinone with Antileukemic Activity (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1003-1009 
    Details
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; Calphostin C ; HPLC ; perylenequinone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To examine the pharmacokinetic features and metabolism of calphostin C, a naturally occurring perylenequinone with potent antileukemic activity. Methods. HPLC-based quantitative detection methods were used to measure calphostin C levels in lysates of leukemic cells and in plasma of mice treated with calphostin C. The plasma concentration-time data were analyzed using the WinNonlin program. In vitro esterases and a microsome P450 preparation in conjunction with a LC-MS(API-EI) system were used to study the metabolism of calphostin C. Results. An intracellular exposure level (AUC0−6h) of 257 μM·h was achieved after in vitro treatment of NALM-6 cells with calphostin C at a 5 μM final concentration in culture medium. After intraperitoneal (i.p.) injection of a 40 mg/kg nontoxic bolus dose of calphostin C, the estimated Cmax was 2.9 μM, which is higher than the effective in vitro concentration of calphostin C against leukemic cells. Drug absorption after i.p. administration was rapid with an absorption half-life of 24.2 min and the estimated tmax was 63.0 min. Calphostin C was cleared with an elimination half-life of 91.3 min. An inactive and smaller metabolite (calphostin B) was detected in plasma of calphostin C-treated mice with a tmax of 41.3 min. Esterase (but not P450) treatment of calphostin C in vitro yielded an inactive metabolite (calphostin B) of the same size and elution profile. Conclusions. Target plasma calphostin C concentrations of potent antileukemic activity can be reached in mice at nontoxic dose levels. This pilot pharmacokinetic study of calphostin C combined with the availability of the described quantitative HPLC method for its detection in cells and plasma provide the basis for future preclinical evaluation of calphostin C and its potential as an anti-leukemic drug.
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    URL: http://dx.doi.org/10.1023/A:1018923430094
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  • 36
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    Electronic Resource
    Improved Lipid Lowering Activity of Bezafibrate Following Continuous Gastrointestinal Administration: Pharmacodynamic Rationale for Sustained Release Preparation of the Drug (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1093-1097 
    Details
    ISSN: 1573-904X
    Keywords: bezafibrate ; hyperlipidemia ; pharmacodynamics ; pharmacokinetics ; sustained release
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To evaluate the role of different routes and modes of administration of bezafibrate (BZF) on its hypolipidemic activity. We hypothesize that the major sites of BZF action are located presystemically as in other 'gastrointestinal (GI) drugs.' Thus, continuous administration of the drug to the GI tract is expected to augment its efficacy and provides a rationale for an oral sustained release preparation of the drug. Methods. The hypothesis was investigated in three experimentally induced-hyperlipidemia rat models. Models A and B were based on cholesterol-enriched diets and Model C on induced acute hyperlipidemia by triton 225 mg/kg. The pharmacokinetics and the pharmacodynamics of the drug following various modes of administration were examined. Results. In all cases, continuous administration of the drug into the duodenum (IGI) at a dose of 30 mg/kg/day for 3 days (Models A and B) or over 18 hr (Model C) reduced significantly both total cholesterol and triglycerides levels and elevated HDL cholesterol levels in comparison to bolus oral administration of the same dose, as well as in comparison to equivalent intravenous infusion (Model C). Infusion of the drug directly into the portal vein produced an equivalent activity to IGI administration. The pharmacokinetic study showed 100% oral bioavailability, good colonic absorption properties and an indication for an enterohepatic cycle. Conclusions. The results confirm that BZF has a first pass hepatic pharmacodynamic effect. Administration of BZF in a slow release matrix tablet to the rats produced the same magnitude of effect as IGI administration, thus proving the pharmacodynamic rationale for this mode of administration for GI drugs.
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    URL: http://dx.doi.org/10.1023/A:1018900219616
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  • 37
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    Electronic Resource
    Dopamine release in the prefrontal cortex in response to memantine following sub-chronic NMDA receptor blockade with memantine: a microdialysis study in rats (1999)
    Springer
    Journal of neural transmission 106 (1999), S. 803-818 
    Details
    ISSN: 1435-1463
    Keywords: Keywords: Dopamine ; memantine ; microdialysis ; pharmacokinetics ; pre-frontal cortex.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary. Memantine is an uncompetitive N-methyl-D-aspartate receptor antagonist which blocks the NMDA receptor with moderate-affinity in a use- and voltage dependent manner. In clinical practice it is used chronically in the treatment of dementia and does not induce psychotomimetic effects as, high affinity, uncompetitive antagonists. Thus, it was of interest to determine dopamine (DA) and metabolite (DOPAC – dihydroxyphenylacetic acid and HVA – homovanillic acid) concentrations in the prefrontal cortex (PFC) in response to 14 days administration of memantine (20 mg/kg/day). It was previously determined that in rats this treatment induces sensitization to the locomotor effect and tolerance to the learning impairing properties of high doses of memantine. Acute administration of memantine (20 mg/kg, ip) did not affect dopamine levels in the PFC. It did however increase DA metabolite (DOPAC and HVA) concentrations. Administration of memantine (20 mg/kg/day) for 14 days before the acute challenge only slightly changed memantine's effect on PFC neurochemistry even though pharmacokinetic tolerance was observed. When memantine was administered to the sham group, which had been repeatedly treated with Hypnorm (including neuroleptic), an increase in PFC dopamine and metabolite content was seen. In accordance with the fact that memantine does not possess psychotomimetic activity at therapeutically relevant doses, these experiments showed that it does not affect the prefrontal cortex dopamine levels.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s007020050201
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  • 38
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    Electronic Resource
    Pharmacokinetics of sterically stabilized hexadecylphosphocholine liposomes versus conventional liposomes and free hexadecylphosphocholine in tumor-free and human breast carcinoma bearing mice (1999)
    Springer
    Breast cancer research and treatment 58 (1999), S. 71-80 
    Details
    ISSN: 1573-7217
    Keywords: hexadecylphosphocholine ; human breast carcinoma ; pharmacokinetics ; sterically stabilized liposomes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The pharmacokinetics of free and different liposomal formulations of hexadecylphosphocholine (HPC) was investigated in tumor-bearing (human mammary tumor MaTu) and tumor-free mice after intravenous and intraperitoneal administration. The levels of HPC were evaluated at different times in serum, normal tissues, and tumor. The purpose was to test the hypothesis that the enhanced therapeutic efficacy of sterically stabilized HPC liposomes in comparison to conventional vesicles and free HPC is due to its pharmacokinetics. Conventional non-compartmental pharmacokinetic analysis and an elaborate three- and four-compartmental model were used for explaining the experimental data. The serum levels of HPC obtained with sterically stabilized liposomes were only consistently higher in comparison to conventional vesicles and free HPC in the first 4 h. In the xenografted MaTu carcinoma, the differences of the HPC content between the different groups are unexpectedly low and do not reflect the high therapeutic activity [5] of sterically stabilized HPC liposomes. Detailed analysis shows that the liposomally encapsulated drug displays a modified pharmacokinetic behavior, which may also involve lymphatic absorption of the liposomal drug.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006224611505
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  • 39
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    Electronic Resource
    Aging effects on drug disposition and effect (1999)
    Springer
    Geriatric nephrology and urology 9 (1999), S. 15-19 
    Details
    ISSN: 1573-7306
    Keywords: aging ; creatinine clearance ; drug deposition ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008333511884
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  • 40
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    Electronic Resource
    Cytochrome P450 Enzymes and Drug Metabolism—Basic Concepts and Methods of Assessment (1999)
    Springer
    Cellular and molecular neurobiology 19 (1999), S. 309-323 
    Details
    ISSN: 1573-6830
    Keywords: cytochrome P450 ; enzyme inhibition ; enzyme induction ; pharmacokinetics ; drug interaction ; in vitro assessment ; clinical assessment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract 1. The cytochrome P450 enzyme family is one of the major drug metabolizing systems in man. 2. Factors such as age, gender, race, environment, and drug treatment may have considerable influence on the activity of these enzymes. 3. There are now well-established in vitro techniques for assessing the role of specific cytochrome P450 enzymes in the metabolism of drugs, as well as the inhibitory or inducing effects of drugs on enzyme activity. In vitro data have been utilized to predict clinical outcomes (i.e., pharmacokinetic interactions), with close correlations between in vitro and in vivo data. 4. This information can be of considerable practical assistance to clinicians, to help with rational prescribing or to prevent or minimize the potential for drug interactions.
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    URL: http://dx.doi.org/10.1023/A:1006993631057
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  • 41
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    Electronic Resource
    Chirality and Drugs Used in Psychiatry: Nice to Know or Need to Know? (1999)
    Springer
    Cellular and molecular neurobiology 19 (1999), S. 355-372 
    Details
    ISSN: 1573-6830
    Keywords: enantiomers ; racemic ; chiral ; stereoselective ; pharmacokinetics ; cytochrome P450 ; geometric isomers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract 1. Many drugs used to treat psychiatric disorders contain a chiral center or a center of unsaturation and are marketed as a mixture of the resultant enantiomers or geometric isomers, respectively. These enantiomers or geometric isomers may differ markedly with regard to their pharmacodynamic and/or pharmacokinetic properties. 2. Examples of the effects of chiral centers or geometric centers on such properties are given for drugs from the following classes: antidepressants (tricyclics, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, viloxazine, bupropion, trazodone, mianserin, venlaflaxine); benzodiazepines, zoplicone, and antipsychotics. 3. As described in this review, there are several notable examples of psychiatric drugs currently available where the individual enantiomers or geometric isomers differ considerably with regard to factors such as effects on amine transport systems, interactions with receptors and metabolizing enzymes, and clearance rates from the body. Indeed, relatively recent developments in analytical and preparative resolution of racemic and geometric drug mixtures and increased interest in developing new drugs which interact with specific targets, which have been described in detail at the molecular level, have resulted in increased emphasis on stereochemistry in drug development.
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    URL: http://dx.doi.org/10.1023/A:1006997731966
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  • 42
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    Electronic Resource
    Metabolism and Pharmacokinetics of Selective Serotonin Reuptake Inhibitors (1999)
    Springer
    Cellular and molecular neurobiology 19 (1999), S. 443-466 
    Details
    ISSN: 1573-6830
    Keywords: selective serotonin reuptake inhibitors ; metabolism ; pharmacokinetics ; fluoxetine ; fluvoxamine ; paroxetine ; sertraline ; citalopram ; cytochrome P450
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract 1. Five drugs with the predominant pharmacologic effect of inhibiting the neuronal reuptake of serotonin are available worldwide for clinical use. This class of psychoactive drugs, known as selective serotonin reuptake inhibitors (SSRIs), is comprised of fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram. 2. The SSRIs appear to share similar pharmacodynamic properties which translate to efficacy in the treatment of depression and anxiety syndromes. The drugs are differentiated by their pharmacokinetic properties with regard to stereochemistry, metabolism, inhibition of cytochrome enzymes, and participation in drug–drug interactions. Studies focusing on the relationship of plasma drug concentration to therapeutic and adverse effects have not confirmed the value of plasma concentration monitoring. 3. This review summarizes the metabolism and relevant pharmacokinetic properties of the SSRIs.
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    URL: http://dx.doi.org/10.1023/A:1006934807375
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  • 43
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    Electronic Resource
    Metabolism of Tricyclic Antidepressants (1999)
    Springer
    Cellular and molecular neurobiology 19 (1999), S. 373-409 
    Details
    ISSN: 1573-6830
    Keywords: antidepressants ; tricyclic ; metabolism ; hydroxy metabolites ; pharmacokinetics ; pharmacogenetics ; drug–drug interactions ; toxicity ; plasma concentrations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract 1. Despite the considerable advances in the treatments available for mood disorders over the past generation, tricyclic antidepressants (TCAs) remain an important option for the pharmacotherapy of depression. 2. The pharmacokinetics of TCAs are characterized by substantial presystemic first-pass metabolism, a large volume of distribution, extensive protein binding, and an elimination half-life averaging about 1 day (up to 3 days for protriptyline). 3. Clearance of tricyclics is dependent primarily on hepatic cytochrome P450 (CYP) oxidative enzymes. Although the activities of some P450 isoenzymes are largely under genetic control, they may be influenced by external factors, such as the concomitant use of other medications or substances. Patient variables, such as ethnicity and age, also affect TCA metabolism. The impact of gender and related reproductive issues is coming under increased scrutiny. 4. Metabolism of TCAs, especially their hydroxylation, results in the formation of active metabolites, which contribute to both the therapeutic and the adverse effects of these compounds. 5. Renal clearance of the polar metabolites of TCAs is reduced by normal aging, accounting for much of the increased risk of toxicity in older patients. 6. Knowledge of factors affecting the metabolism of TCAs can further the development and understanding of newer antidepressant medications.
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    URL: http://dx.doi.org/10.1023/A:1006949816036
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  • 44
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    Electronic Resource
    Distribution of a 20-Mer Phosphorothioate Oligonucleotide, CGP69846A (ISIS 5132), into Airway Leukocytes and Epithelial Cells Following Intratracheal Delivery to Brown-Norway Rats (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1542-1549 
    Details
    ISSN: 1573-904X
    Keywords: antisense ; Brown-Norway rat ; oligodeoxynucleotide ; pulmonary delivery ; ISIS 2105 ; pharmacokinetics ; airway inflammation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To evaluate the pulmonary distribution of CGP69846A (ISIS 5132), a phosphorothioate oligonucleotide, following intra-tracheal (i.t.) instillation into Brown-Norway rats. Methods. The pharmacokinetic profile of [3H]-CGP69846A was investigated following i.t. instillation into both naïve and inflamed airways of Brown-Norway rats. The cellular distribution was determined using autoradiography, immunohistochemistry and flow cytometry/fluorescence microscopy, in inflamed airways. Results. CGP69846A displayed a dose-dependent lung retention following i.t. administration which was unaffected by local inflammation. Autoradiography and immunohistochemistry showed distribution to alveolar macrophages, eosinophils, bronchial and tracheal epithelium and alveolar cells. Studies with [FITCJ-CGP69846A demonstrated a preferential association of oligonucleotide with leukocytes in bronchial lavage fluid of: macrophages 〉 eosinophils = neutrophils 〉 〉 lymphocytes. Conclusions. The dose-dependency of lung retention together with cell-specific uptake suggests that the lung can be used as a local target for antisense molecules with potentially minimal systemic effects. Furthermore, the preferential targeting of macrophages and the airway epithelium by oligonucleotides may represent rational cellular targets for antisense therapeutics.
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    URL: http://dx.doi.org/10.1023/A:1015048419558
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  • 45
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    Electronic Resource
    Analyzing Rich Data Using Different Methods Provided by NONMEM: Pharmacokinetics of Telmisartan Following Intravenous Infusion to Healthy Volunteers (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 772-776 
    Details
    ISSN: 1573-904X
    Keywords: nonlinear mixed effects modeling (NONMEM) ; pharmacokinetics ; telmisartan ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011997229669
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  • 46
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    Electronic Resource
    Pharmacokinetics and Tissue Disposition in Monkeys of an Antisense Oligonucleotide Inhibitor of Ha-Ras Encapsulated in Stealth Liposomes (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1309-1315 
    Details
    ISSN: 1573-904X
    Keywords: antisense phosphorothioate oligonucleotide ; stealth liposome ; pharmacokinetics ; monkey ; capillary gel electrophoresis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. This study examined the pharmacokinetics and tissue distribution of an antisense oligonucleotide ISIS 2503, formulated in stealth (pegylated) liposomes (encapsulated) or in phosphate-buffered saline (unencapsulated). Methods. Encapsulated or unencapsulated ISIS 2503 was administered to rhesus monkeys by intravenous infusion. The concentrations of ISIS 2503 and metabolites in blood, plasma, and tissue samples were determined by capillary gel electrophoresis. Results. Plasma concentrations of encapsulated ISIS 2503 decreased mono-exponentially after infusion with a mean half-life of 57.8 hours. In contrast, the concentration of unencapsulated ISIS 2503 in plasma decreased rapidly with a mean half-life of 1.07 hours. Both encapsulated and unencapsulated ISIS 2503 distributed widely into tissues. Encapsulated ISIS 2503 distributed primarily to the reticulo-endothelial system and there were few metabolites observed. In contrast, unencapsulated ISIS 2503 distributed rapidly to tissue with highest concentration seen in kidney and liver. Nuclease-mediated metabolism was extensive for unencapsulated oligonucleotide in plasma and tissues. Conclusions. The data suggest that stealth liposomes protect ISIS 2503 from nucleases in blood and tissues, slow tissue uptake, and slow the rate of clearance from the systemic circulation. These attributes may make these formulations attractive for delivering oligonucleotides to sites with increased vasculature permeability such as tumors or sites of inflammation.
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    URL: http://dx.doi.org/10.1023/A:1014822219133
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  • 47
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of Aminolevulinic Acid After Intravesical Administration to Dogs (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 288-295 
    Details
    ISSN: 1573-904X
    Keywords: aminolevulinic acid ; intravesical ; pharmacokinetics ; photodiagnosis ; bladder ; cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To examine the stability and systemic absorption of aminolevulinic acid (ALA) in dogs during intravesical administration. Methods. Nine dogs received an intravesical dose of ALA either with no prior treatment, after receiving ammonium chloride for urinary acidification, or after receiving sodium bicarbonate for urinary alkalinization. Urine and blood samples collected during and after administration were monitored for ALA using an HPLC assay developed in our laboratories. Concentrations of pyrazine 2,5-dipropionic acid, the major ALA degradation product, and radiolabeled inulin, a nonabsorbable marker for urine volume, were also determined. Results. Less than 0.6% of intravesical ALA doses was absorbed into plasma. Urine concentrations decreased to 37% of the initial concentration during the 2 hour instillation. Decreases in urinary ALA and radiolabeled inulin concentrations were significantly correlated, indicating that urine dilution accounted for over 80% of observed decreases in urinary ALA. ALA conversion to pyrazine 2,5-dipropionic acid was negligible. Conclusions. These studies demonstrate that ALA is stable and poorly absorbed into the systemic circulation during intravesical instillation. Future studies utilizing intravesical ALA for photodiagnosis of bladder cancer should include measures to restrict fluid intake as a means to limit dilution and maximize ALA concentrations during instillation.
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    URL: http://dx.doi.org/10.1023/A:1018840827910
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  • 48
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    Electronic Resource
    Characterization of Ocular Pharmacokinetics of Beta-Blockers Using a Diffusion Model After Instillation (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1596-1601 
    Details
    ISSN: 1573-904X
    Keywords: diffusion model ; drug delivery system ; ocular penetration ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To characterize the ocular pharmacokinetics of beta-blockers (timolol and tilisolol) after instillation in the albino rabbit using a mathematical model that includes a diffusion process. Methods. The disposition of fluorescein isothiocyanate-dextran (FITC-dextran, molecular weight 4400), timolol, and tilisolol was determined in tear fluid and aqueous humor after instillation or ocular injection in rabbits. The in vivo penetration parameters were estimated by fitting the concentration-time profiles to the Laplace equations based on a diffusion model using MULTI(FILT) program. Thein vivo permeability of drugs was measured across cornea using a two-chamber diffusion cell. Results. Concentration-time profiles of drugs in the tear fluid after instillation showed a monoexponential curve. Although a monoexponential curve was observed in the aqueous humor concentration of FITC-dextran after injection into the aqueous chamber, timolol and tilisolol showed a biexponential curve. On the basis of these results, anin vivo pharmacokinetic model was developed for estimation of penetration parameters. The in vitro partition parameters were higher than those of the in vivo parameters. Conclusions. The ocular absorption of timolol and tilisolol was characterized using an in vivo pharmacokinetic model and in vivo penetration parameters.
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    URL: http://dx.doi.org/10.1023/A:1018964823193
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  • 49
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    A Pharmacokinetic Model for Tenidap in Normal Volunteers and Rheumatoid Arthritis Patients (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1608-1615 
    Details
    ISSN: 1573-904X
    Keywords: tenidap ; pharmacokinetics ; EM algorithm ; nonlinear mixed-effects modelling ; covariates
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To develop a pharmacokinetic model for tenidap and to identify important relationships between the pharmacokinetic parameters and available covariates. Methods. Plasma concentration data from several phase I and phase II studies were used to develop a pharmacokinetic model for tenidap, a novel anti-rheumatic drug. An appropriate pharmacokinetic model was selected on the basis of individual nonlinear regression analyses and an EM algorithm was used to perform a nonlinear mixed-effects analysis. Scatter plots of posterior individual pharmacokinetic parameters were used to identify possible covariate effects. Results. Predicted responses were in good agreement with the observed data. A bi-exponential model with zero order absorption was subsequently used to develop the mixed-effects model. Covariate relationships selected on the basis of differences in the objective function, although statistically significant, were not particularly strong. Conclusions. The pharmacokinetics of tenidap can be described by a bi-exponential model with zero order absorption. Based on differences in the log-likelihood, significant covariate-parameter relationships were identified between smoking and CL, and between gender and Vss and CLd. Simulated sparse data analyses indicated that the model would be robust for the analysis of sparse data generated in observational studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018969024101
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  • 50
    Electronic Resource
    Electronic Resource
    Safety and Toxicokinetics of Intravenous Liposomal Amphotericin B (AmBisome ®) in Beagle Dogs (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1694-1701 
    Details
    ISSN: 1573-904X
    Keywords: amphotericin B ; liposomes ; pharmacokinetics ; tissue distribution ; toxicity ; toxicokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Amphotericin B (AmB) in small, unilamellar liposomes (AmBisome ®) has an improved therapeutic index, and altered pharmacokinetics. The repeat-dose safety and toxicokinetic profiles of AmBisome were studied at clinically relevant doses. Methods. Beagle dogs (5/sex/group) received intravenous AmBisome (0.25, 1,4, 8, and 16 mg/kg/day), empty liposomes or vehicle for 30 days. AmB was determined in plasma on days 1, 14, and 30, and in tissues on day 31. Safety parameters included body weight, clinical chemistry, hematology and microscopic pathology. Results. Seventeen of twenty animals receiving 8 and 16 mg/kg were sacrificed early due to weight loss caused by reduced food intake. Dose-dependent renal tubular nephrosis, and other effects characteristic of conventional AmB occurred at 1 mg/kg/day or higher. Although empty liposomes and AmBisome increased plasma cholesterol, no toxicities unique to AmBisome were revealed. Plasma ultrafiltrates contained no AmB. AmBisome achieved plasma levels 100-fold higher than other AmB formulations. AmBisome kinetics were non-linear, with clearance and distribution volumes decreasing with increasing dose. This, and nonlinear tissue uptake, suggest AmBisome disposition was saturable. Conclusions. AmBisome has the same toxic effects as conventional AmB, but they appear at much higher plasma exposures. AmBisome's non-linear pharmacokinetics are not associated with increased risk, as toxicity increases linearly with dosage. Dogs tolerated AmBisome with minimal to moderate changes in renal function at doses (4 mg/kg/day) producing peak plasma concentrations of 18−94 µg/mL.
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    URL: http://dx.doi.org/10.1023/A:1018997730462
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  • 51
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    Electronic Resource
    Modeling of Pharmacokinetic/Pharmacodynamic (PK/PD) Relationships: Concepts and Perspectives (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 176-185 
    Details
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; pharmacodynamics ; pharmacology ; modeling
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Pharmacokinetic/pharmacodynamic (PK/PD)-modeling links dose-concentration relationships (PK) and concentration-effect relationships (PD), thereby facilitating the description and prediction of the time course of drug effects resulting from a certain dosing regimen. PK/PD-modeling approaches can basically be distinguished by four major attributes. The first characterizes the link between measured drug concentration and the response system, direct link versus indirect link. The second considers how the response system relates effect site concentration to the observed outcome, direct versus indirect response. The third regards what clinically or experimentally assessed information is used to establish the link between concentration and effect, hard link versus soft link. And the fourth considers the time dependency of pharmacodynamic model parameters, distinguishing between time-variant versus time-invariant. Application of PK/PD-modeling concepts has been identified as potentially beneficial in all phases of preclinical and clinical drug development. Although today predominantly limited to research, broader application of PK/PD-concepts in clinical therapy will provide a more rational basis for patient-specific dosage individualization and may thus guide applied pharmacotherapy to a higher level of performance.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011907920641
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  • 52
    Electronic Resource
    Electronic Resource
    Influence of Crystal Habit on Trimethoprim Suspension Formulation (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 261-265 
    Details
    ISSN: 1573-904X
    Keywords: crystal habit ; trimethoprim suspension ; physical stability ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The role of crystal habit in influencing the physical stability and pharmacokinetics of trimethoprim suspensions was examined. Methods. Different habits of trimethoprim (TMP) were obtained by recrystallizing the commercial sample (PD) utilizing solvent-change precipitation method. Four distinct habits (microscopic observation) belonging to the same polymorphic state (DSC studies) were selected for studies. Preformulation and formulation studies were carried out on suspension dosage forms containing these crystals. The freshly prepared suspensions were also evaluated for their pharmacokinetic behaviour on healthy human volunteers using a cross over study. Results. Variation of crystallization conditions produces different habits of TMP. Among the different crystal habits exhibiting same polymorphic state, the most anisometric crystal showed best physical stability in terms of sedimentation volume and redispersibility. However, habit did not significantly affect the extent of TMP excreted in urine. Conclusions. Modification of surface morphology without significantly altering the polymorphic state can be utilized for improving physical stability of TMP suspensions. However, the pharmacokinetic profile remains unaltered.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018832526093
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  • 53
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    Electronic Resource
    Effects of Hyperlipidemia on the Pharmacokinetics of Nifedipine in the Rat (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 309-313 
    Details
    ISSN: 1573-904X
    Keywords: hyperlipidemia ; hypercholesterolemia ; nifedipine ; pharmacokinetics ; protein binding ; rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The effect of hyperlipidemia on nifedipine pharmacokinetics was studied. The mechanisms by which hyperlipidemia affects pharmacokinetics of drugs are mainly undetermined. Hyperlipidemia may decrease the fraction of unbound drug in plasma and/or decrease intrinsic ability of the cytochrome P-450 systems due to excess membrane cholesterol. Hyperlipidemia is a primary risk factor for coronary artery disease leading to hypertension and ischemic heart disease, for which nifedipine, a calcium channel blocker, is used. Methods. Poloxamer 407 (P407)-induced hyperlipidemic rat model was used to study the effects of hyperlipidemia on the pharmacokinetics of nifedipine (6 mg kg−1 given iv, ip and po). Total plasma cholesterol levels increased from 0.82−2.02 to 5.27−11.05 mmol L−1 48 h post P407 administration (Ig kg−1, ip). Protein binding studies were conducted by an ultrafiltration method. Results. Hyperlipidemia significantly decreased CLTB by 38% and CLTB/F by 45 and 42% following po and ip doses, respectively, thereby increasing AUC0−∞, Cmax and half-life. Absolute bioavailability and Vdss remained unchanged. AUC0−∞ was affected to the same extent in each route of administration, therefore, the effect was mainly systemic rather than presystemic. Hyperlipidemia significantly lowered the fraction unbound in plasma by approximately 31%. Conclusions. The altered pharmacokinetics of nifedipine by P407-induced HYPERLIPIDEMIA may be, at least in part, due to the decrease in fraction unbound in plasma. A decrease in intrinsic clearance, however, cannot be ruled out.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018896912889
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  • 54
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    Electronic Resource
    Pharmacokinetics and Biologic Activity of the Novel Mast Cell Inhibitor, 4-(3′-Hydroxyphenyl)-amino-6,7-dimethoxyquinazoline in Mice (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 117-122 
    Details
    ISSN: 1573-904X
    Keywords: WHI-P180 ; pharmacokinetics ; quinazolines ; mast cell inhibitor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The purpose of the present study was to examine the pharma-codynamic and pharmacokinetic features of the novel mast cell inhibitor 4-(3′-Hydroxyphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P180) in mice. Methods. A high performance liquid chromatography (HPLC)-based quantitative detection method was used to measure plasma WHI-P180 levels in mice. The plasma concentration-time data was fit to a single compartment pharmacokinetic model by using the WinNonlin program to calculate the pharmacokinetic parameters. A cutaneous anaphylaxis model was used to examine the pharmacodynamic effects of WHI-P180 on anaphylaxis-associated vascular hyperpermeability. Results. The elimination half-life of WHI-P180 in CD-1 mice (BALB/ c mice) following i.v., i.p., or p.o. administration was less than 10 min. Systemic clearance of WHI-P180 was 6742 mL/h/kg in CD-1 mice and 8188 mL/h/kg in BALB/c mice. Notably, WHI-P180, when administered in two consecutive nontoxic i.p. bolus doses of 25 mg/kg, inhibited IgE/antigen-induced vascular hyperpermeability in a well-characterized murine model of passive cutaneous anaphylaxis. Conclusions. WHI-P180 is an active inhibitor of IgE-mediated mast cell responses in vitro and in vivo. Further preclinical characterization of WHI-P180 may improve the efficacy of WHI-P180 in vivo and provide the basis for design of effective treatment and prevention programs for mast cell mediated allergic reactions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018835232027
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  • 55
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    Electronic Resource
    Modification of the Pharmacokinetics and Dosage of Cefuroxime by Endotoxin-induced Fever in Buffalo Calves (1999)
    Springer
    Veterinary research communications 23 (1999), S. 361-368 
    Details
    ISSN: 1573-7446
    Keywords: buffalo ; cefuroxime ; dosage ; endotoxin ; excretion ; fever ; pharmacokinetics ; plasma ; urine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effect of endotoxin-induced fever on the pharmacokinetics and dosage regimen of cefuroxime was investigated in buffalo calves following a single intravenous dose of 10 mg/kg body weight. The fever was induced by intravenous administration of E. coli endotoxin at a dose of 1 μg/kg body weight. The distribution and elimination half-lives were 0.100 h and 1.82 h, respectively, in healthy and 0.109 h and 2.28 h, respectively, in febrile buffalo calves. About 91% of the administered dose was excreted in the urine within 24 h. There was no effect of fever on the plasma protein binding of cefuroxime. The dosage regimen for intravenous administration of cefuroxime may be reduced in febrile conditions but the probability of this was only 0.3.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006385624850
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  • 56
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    Electronic Resource
    Enzymatic and pharmacokinetic studies on the metabolism of branched chain α-keto acids in the rat (1983)
    Springer
    European journal of nutrition 22 (1983), S. 14-26 
    Details
    ISSN: 1436-6215
    Keywords: branched chain α-keto acids ; 4-methyl-2-oxopentanoate, 3-methyl-2-oxopentanoate ; 3-methyl-2-oxobutyrate ; dehydrogenation ; transamination ; pharmacokinetics ; absorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Medicine
    Description / Table of Contents: Zusammenfassung Michaelis-Konstanten und Aktivitäten von Dehydrogenasen und Transaminasen der drei verzweigten α-Ketosäuren Keto-Valin, Keto-Leucin und Keto-Isoleucin in Leber, Niere, Skeletmuskel und Gehirn von Ratten werden mitgeteilt. Nach oraler Zufuhr passieren nur 11–22% der Ketosäuren unverändert die Leber. Aus pharmakokinetischen und Resorptions-Untersuchungen erhaltene Blutspiegel an Ketosäuren werden zu den Michaelis-Konstanten in Beziehung gesetzt. Bei den geringen Konzentrationen an Ketosäuren nach oraler Zufuhr kann angenommen werden, daß die oxidativen Prozesse in den nichthepatischen Geweben über die Transaminierung überwiegen. Daten über die Wachstumseffizienz von verzweigtkettigen α-Ketosäuren im Vergleich zu den entsprechenden Aminosäuren stimmen mit dieser Vorstellung überein. Bei intravenöser Verabreichung müßten die Voraussetzungen für Transaminierung besser sein als nach oraler Zufuhr. Auf der Basis von Daten aus der Literatur werden die Übertragbarkeit unserer Befunde auf den Menschen und die verschiedenen Faktoren, welche die Effizienz der verzweigten α-Ketosäuren durch Einwirkung auf ihren Stoffwechsel beeinflussen können, diskutiert.
    Notes: Summary Miehaelis-constants and enzyme activities for dehydrogenation and transamination of the three branched chainα-keto acids in liver, kidney, skeletal muscle, and brain of rats are reported. After oral load only 11–22 % of the keto acids pass the liver unchanged. Blood levels in pharmacokinetic and absorption studies are related to the Michaelis-constants. At the low keto-acid concentrations after oral application, dehydrogenation in the non-hepatic tissues is supposed to prevail over transamination. Data on feed efficiency of branched chain α-keto acids reported in the literature support this view. The chance for transamination is better after intravenous administration. The transferability of our data to humans, and various factors influencing the efficiency of branched chain α-keto acids are discussed in connection with data reported in the literature.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02020781
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  • 57
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    Electronic Resource
    The bioavailability of circulating antibody-bound insulin following insulin withdrawal in Type I (insulin-dependent) diabetes (1983)
    Springer
    Diabetologia 24 (1983), S. 355-358 
    Details
    ISSN: 1432-0428
    Keywords: Type 1 diabetes ; insulin ; insulin antibody ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Insulin withdrawal studies were performed in 12 Type 1 (insulin-dependent) C-peptide negative diabetic patients with low to moderate insulin antibody levels, to assess the biological availability of antibody-bound insulin and its clinical significance. There was a highly significant correlation between the extent to which the free insulin concentration was maintained during the period of insulin withdrawal and both the level of insulin-binding by serum and the total insulin concentration at the start of the study. During insulin withdrawal, the patients who best maintained their circulating free insulin levels showed the smallest increases in blood glucose and 3-hydroxybutyrate concentrations. We conclude that antibody-bound insulin is available for physiological action, and that in those individuals with moderate antibody concentrations it is capable, in the fasting state, of maintaining free insulin levels. In these circumstances insulin antibodies are behaving as simple carrier proteins.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00251824
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  • 58
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    Electronic Resource
    Pharmacodynamic and pharmacokinetic evaluation in man of the new sympathomimetic amezinium (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 185-190 
    Details
    ISSN: 1432-1041
    Keywords: amezinium ; hypotension ; antihypotensive drug ; ECG ; concentration-effect relationship ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Blood pressure, ECG and plasma concentration were determined for up to 12h following single i.v. (10 mg) and oral (20 mg) doses of amezinium (Regulton®) in 8 healthy, male volunteers. The i.v. and oral doses were almost equi-active in significantly increasing systolic blood pressure (SBP) by 14.5 and 15.6 mmHg, respectively. The maximum SBP after the i.v. dose was reached after 45 min, and 105 min after oral administration. The heart rate fell reflexly. The increases in mean and diastolic blood pressures were not significant. Pulse pressure was enhanced after both i.v. and oral administration. The effect on systolic blood pressure lasted for about 4 h. There was a slight shortening of the QTc duration, which could not be explained as a drug effect. Other ECG time intervals were not altered. Multiple regression analysis showed a significant positive correlation between the log plasma concentration and the increase in SBP between 0.5 and 5 h after oral administration (r=0.78,p〈0.001) and between 0.75 and 5 h after i.v. administration (r=0.83,p〈0.001). 30 min after amezinium p.o. the mean SBP began to rise, when a plasma level of about 30 ng/ml was reached.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00613815
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  • 59
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    Electronic Resource
    Plasma levels of sulfinpyrazone and of two of its metabolites after a single dose and during the steady state (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 231-235 
    Details
    ISSN: 1432-1041
    Keywords: sulfinpyrazone ; pharmacokinetics ; metabolites ; inhibition of platelet aggregation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of sulfinpyrazone, and the plasma levels of its sulfide and sulfone metabolites, have been determined after a single oral dose (400 mg) and during steady-state conditions (4×200 mg daily for 6 days) in healthy female volunteers. The plasma half-lives of sulfinpyrazone, the sulfone and the sulfide were 3.7, 3.2 and 14.7 h, respectively, during steady-state. After a single dose and during steady state conditions the half-lives of sulfinpyrazone and the sulfone did not differ significantly. The trough plasma levels of the sulfide metabolite exceeded those of the parent compound in four of the six volunteers on the last day of the study. The data suggest that in man the most likely candidate for the prolonged inhibition of platelet aggregation observed after treatment with sulfinpyrazone is its sulfide metabolite, because of its prolonged elimination.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00613823
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  • 60
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    Electronic Resource
    Clinical effect and pharmacokinetics of trimethoprim-sulphadiazine in children with urinary tract infections (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 267-271 
    Details
    ISSN: 1432-1041
    Keywords: trimethoprim ; sulphadiazine ; urinary tract infection ; children ; pharmacokinetics ; urinary concentrations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The clinical effect and pharmacokinetics of the combination trimethoprim (TMP)-sulphadiazine (SD) were studied in 18 children with acute urinary tract infections (UTI), aged 2–56 months. A suspension of TMP-SD (9+41 mg/ml) was taken orally twice daily for 10 days. Various doses of TMP (2.9–3.7 mg/kg/day) and SD (12.9–16.7 mg/kg/day) were also given to children of different ages. After 2–4 days of treatment, bacterial cultures of urine were negative and C-reactive protein in serum, WBC count and ESR in all patients had become normal. Steady state serum levels for both components were reached after 4 or more days of treatment. At steady state, mean peak serum concentrations of TMP and SD of 1.4 µg/ml and 27 µg/ml, respectively, were found within 2–4 h after a fasting morning dose. The biological half-lives of TMP and SD were of the same order of magnitude, but the total clearance of TMP was 5 times greater than that of SD. The concentrations of TMP-SD in urine were invariably more than 10 times the minimum inhibitory concentrations (MIC) for the causative organisms (tested at the ratios 1:20 and 1:4 of TMP and SD). Non-metabolized SD constituted 77% of total SD in urine of infants, and 55% of total SD in children of 1 year or more. The TMP-SD combination showed a satisfactory clinical effect and favourable pharmacokinetic properties in children with UTI.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00613830
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  • 61
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    Electronic Resource
    Pharmacodynamic and pharmacokinetic interactions between ketamine and diazepam (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 337-343 
    Details
    ISSN: 1432-1041
    Keywords: ketamine ; diazepam ; drug interaction ; pharmacokinetics ; premedication ; clorazepate ; drug metabolism ; enzyme induction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Anaesthesia with continuous i.v. ketamine and 65% nitrous oxide in oxygen was given to a total of 49 patients undergoing major abdominal surgery. A control group was premedicated with atropine and other groups received in addition rectal diazepam or clorazepate i.v. Four further patients had been on oral diazepam or barbiturates for 1–14 years; as premedication they received atropine alone. The anaesthetic technique gave good operative conditions in the 4 groups of patients. The haemodynamic stimulation of ketamine was significantly reduced in patients premedicated with diazepam. Psychotomimetic side effects were not prominent in any of the groups. Patients premedicated with diazepam required a lower rate of ketamine infusion as compared to controls during the initial 30 min of anaesthesia. The patients in the other groups did not differ from the control group in this respect. There were large differences in metabolic pattern between the groups. As compared to the controls, the patients on long-term diazepam or barbiturates had high concentrations of hydroxylated metabolites, with levels higher than that of norketamine. The patients pretreated with diazepam had very low plasma levels of hydroxylated metabolites. Clorazepate premedication did not significantly affect the metabolism of ketamine. The biological half-life of ketamine was significantly increased in the diazepam-treated group, and it was shortened in those on long term treatment with barbiturates or diazepam.
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    URL: http://dx.doi.org/10.1007/BF00610051
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  • 62
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    Electronic Resource
    Serum concentrations of amiodarone during long term therapy. Relation to dose, efficacy and toxicity (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 485-494 
    Details
    ISSN: 1432-1041
    Keywords: amiodarone ; pharmacokinetics ; therapeutic serum level ; thyroid function ; antiarrhythmic therapy ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 17 patients on long term therapy with amiodarone, serum drug levels measured by HPLC were related to pharmacological effects. At steady state, serum levels were directly proportional to the dose, 5 mg/kg per day leading to an average serum level of approximately 2.5 µmol/l. The non-amiodarone level of iodine averaged 4-times higher than the level of amiodarone iodine. The elimination half-life of amiodarone ranged from 21 to 78 days, and of non-amiodarone iodine from 24 to 160 days. Control of arrhythmias was satisfactory in all 12 evaluable patients, when the serum amiodarone level exceeded 1.5 µmol/l. Deterioration of vision and polyserositis occurred only at amiodarone levels above 4 µmol/l. Tentatively, a therapeutic range of 1.5 to 4 µmol/l is proposed. In contrast, thyroid dysfunction was observed at any amiodarone level. In view of the narrow therapeutic window, therapy with amiodarone may be optimized by monitoring its serum level and in addition, thyroid function should be regularly checked.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609891
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  • 63
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    Electronic Resource
    Pharmacokinetics of sotalol during pregnancy (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 521-524 
    Details
    ISSN: 1432-1041
    Keywords: sotalol ; beta-adrenoceptor antagonist ; pregnancy ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Sotalol, a beta-adrenoceptor blocking drug, was administered to 6 healthy pregnant volunteers between 32–36 weeks gestation and when at least 6 weeks post-partum. On both occasions, each volunteer was given sotalol 100 mg intravenously and 400 mg orally in randomised order with at least a 1 week washout period between. Plasma samples were analysed for sotalol using a fluorometric method and the pharmacokinetic profiles investigated. The systemic clearance of sotalol was significantly greater in the antenatal period (2.4±0.3 ml/min/kg) than in the post-natal phase (1.5±0.1 ml/min/kg). The apparent volume of distribution was similar in the two periods: the elimination half-life was 6.6±0.6h ante-natally and 9.3±0.7h post-natally after intravenous drug but the trend for faster elimination was not significant. The elimination half-life after oral administration (about 10h) and bioavailability (about 90%) were not altered significantly by pregnancy. It is suggested that the more rapid clearance of sotalol in pregnancy may be due to increases in renal plasma flow and glomerular filtration rate.
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    URL: http://dx.doi.org/10.1007/BF00609896
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  • 64
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    Electronic Resource
    Pharmacokinetics of biliary excretion in man V (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 549-556 
    Details
    ISSN: 1432-1041
    Keywords: dibromosulfophthalein ; pharmacokinetics ; plasma levels ; urinary excretion ; biliary excretion ; biliary fistula ; enterohepatic circulation ; hepatic transport test
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of dibromosulfophthalein (DBSP), the 3,6-dibromo analogue of BSP, was studied in 7 patients with a biliary fistula, 52 h after cholecystectomy, and in 6 gynaecological patients with an indwelling urethral catheter, following extirpation of the uterus i.e. with an intact enterohepatic circulation. Plasma protein binding determined by ultrafiltration was 98–99% up to a concentration of 700 µg/ml. After an intravenous bolus injection of DBSP 5 mg/kg, a biexponential plasma decay was found in both groups, with a rapid initial t1/2 of 2–6 min and a slow secondary phase of 33–109 min (mean 66 min) in the cholecystectomy patients, and 10–30 min (mean 19 min) in the gynaecological patients. The biliary excretion rate varied considerably between the patients and was highly correlated with bile flow. Biliary output amounted to a maximum of 86% of the dose in 24 h. The excretion rate curves showed ascending and descending phases, the mean terminal t1/2 being 65 min. Urinary excretion was 3–11% of the dose in 8 h in the gynaecological patients (mean 6%) and 6–31% in the cholecystectomy group (mean 16%). Renal clearance of unbound DBSP was about ten-times greater than the glomerular filtration rate, which indicates tubular secretion. A two compartment model with elimination from the peripheral and central compartments was selected because of these data. Analysis of the plasma-disappearance curves indicated an initial plasma clearance of 500–600 ml/min, which suggests that hepatic uptake will be very dependent on flow. Steady state (biliary) clearance was about 400 ml/min in the gynaecological group and approximately half that in the cholecystectomy patients; V1 tended to be higher and V2 to be lower in the latter group. It is concluded that biliary excretion rate of DBSP in patients with a biliary fistula is probably depressed by the postoperative bile drainage and the lack of enterohepatic cycling of bile salts.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609902
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  • 65
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    Electronic Resource
    Pharmacokinetics of hydrochlorothiazide in relation to renal function (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 661-665 
    Details
    ISSN: 1432-1041
    Keywords: hydrochlorothiazide ; pharmacokinetics ; renal failure ; dosage adjustment ; excretory mechanism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of hydrochlorothiazide (HCT) was investigated in 23 subjects with normal renal function or widely varying degrees of renal failure. The half-life of elimination increased from 6.4 h in subjects with normal renal function to 11.5 h in patients with mild renal impairment (endogenous creatinine clearance between 30 and 90 ml/min), and to 20.7 h in patients with an endogenous creatinine clearance below 30 ml/min. The cumulative urinary excretion and the renal HCT clearance were correspondingly reduced in patients with impaired kidney function. In normal subjects HCT was mainly excreted by tubular secretion, but as renal HCT clearance in patients with renal impairment did not differ significantly from endogenous creatinine clearance, it was concluded that the secretory mechanism is most markedly impaired. In patients with an endogenous creatinine clearance of 30 to 90 ml/min, the dosage of HCT should be reduced to 1/2 and in patients with a endogenous creatinine clearance below 30 ml/min to 1/4 of the normal daily dose to avoid dose dependant side-effects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542218
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  • 66
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    Electronic Resource
    The pharmacokinetics of subcutaneous dihydroergotamine with and without a dextran 70 infusion (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 813-818 
    Details
    ISSN: 1432-1041
    Keywords: dihydroergotamine ; dextran 70 ; pharmacokinetics ; radioimmunoassay ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of subcutaneous dihydroergotamine (DHE) with or without dextran 70 infusion was evaluated in a single- and multiple-dose study in 30 patients. Radioimmunoassay was used to measure plasma DHE and the anthrone method to determine the dextran concentration. In the single-dose study no significant interaction between DHE and dextran was noted with respect to their plasma levels. The absorption of s.c. DHE was rapid and the disappearance curve followed a biphasic pattern, t0.5 α being 1.4 and 2.0 h, t0.5 β 22 and 21 h for DHE and DHE/dextran 70, respectively. In the multi-dose study the trough level of DHE initially had a tendency to rise, in accordance with simulated plasma concentration curves. DHE trough levels were about 0.5 ng/ml and were well above the assumed minimum effective value to induce venoconstriction (0.06 ng/ml). Dextran concentrations were significantly higher when DHE was co-administered, possibly, due to changes in plasma volume. It is concluded that DHE 0.5 mg s.c. twice daily will give an adequate plasma concentration and that there was no important interaction between it and infused dextran 70.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00607093
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  • 67
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    Electronic Resource
    Pharmacokinetics of the new analgesic, meptazinol, after oral and intravenous administration to volunteers (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 77-80 
    Details
    ISSN: 1432-1041
    Keywords: meptazinol ; pharmacokinetics ; multiple dosing ; plasma protein binding ; analgesic
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of meptazinol (Meptid®) have been studied in nine male volunteers after single and multiple oral administration of 200 mg tablets and also after a single 25 mg intravenous dose. Plasma concentrations of meptazinol were determined by HPLC using fluorescence detection. Drug absorption after oral dosage was rapid, peak plasma concentrations being reached between 0.25 and 2 h after drug administration. Subsequent elimination proceeded in an apparently mono-exponential fashion with a half-life of 2 h, although after intravenous dosage there was evidence of an initial rapid distributive phase. The mean total plasma clearance was 2.21/min and the mean apparent volume of distribution (Vdβ) was 4.99 l/min. The bioavailability ranged from 1.9 to 18.5% (mean=8.7%) and was related to the rate of absorption. Multiple dosing, 6-hourly for 3 days, did not produce any accumulation above that predicted from a single dose. Plasma protein binding of the drug was 27.1% and did not vary over the therapeutic concentration range of 25 to 250 ng/ml.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00544019
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  • 68
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    Electronic Resource
    Pharmacokinetics and absolute bioavailability of carteolol, a new β-adrenergic receptor blocking agent (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 95-101 
    Details
    ISSN: 1432-1041
    Keywords: carteolol ; pharmacokinetics ; beta-adrenoreceptor blocking drug ; absolute bioavailability ; plasma levels ; urinary excretion ; renal handling
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and absolute bioavailability of a new nonselective β-adrenoreceptor blocking agent, carteolol, were investigated after administration of single intravenous and oral doses to eight normal volunteers. Plasma and urine drug concentrations were measured by an HPLC method. The pharmacokinetic parameters after intravenous dosing were obtained by a two-compartment analysis: elimination or β-phase t1/2 4.7±0.3 h; Vc, 0.74±0.101/kg; Vd, 4.05±0.48 l/kg; Cl, 10.13±0.94 ml/min/kg; ClR, 6.56±0.58 ml/min/kg; and ClNR, 3.57±0.40 ml/min/kg. The absolute bioavailability obtained from plasma data was 83.7±8.0%, which was consistent with that derived from analysis of urine of 82.7±4.2%. The amounts excreted unchanged in urine up to 48 h after the intravenous and oral doses were 65.0±1.5% and 53.8±3.2% of the administered doses, respectively. The t1/2 for removal of the drug derived from plasma and urine findings after intravenous and oral dosing were similar, which indicates that the main route of elimination of carteolol is via the kidneys. As the ClR of carteolol exceeded the Cl of creatinine there may be renal tubular secretion of the drug.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00544023
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  • 69
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    Electronic Resource
    Pharmacokinetics of triamterene after i.v. administration to man: Determination of bioavailability (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 237-241 
    Details
    ISSN: 1432-1041
    Keywords: triamterene ; bioavailability ; pharmacokinetics ; metabolism ; hydroxy triamterene sulphate ; urinary excretion ; i.v. administration ; first-pass-effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary With a new formulation, which made intravenous infusion of triamterene (TA) possible, plasma levels and urinary excretion rates of TA and its main metabolite (OH-TA-ester) were measured in a randomized, cross-over trial in 6 healthy volunteers given triamterene 10 mg i.v. and 50 mg p.o. TA and OH-TA-ester were determined by densitometric measurement of native fluorescence after thin layer chromatography. Distribution volumes of the central compartment of TA and OH-TA-ester were 1.49 l/kg and 0.11 l/kg, respectively. Terminal half-lives were 255 min for TA and 188 min for OH-TA-ester after i.v. administration. For TA total plasma clearance was 4.5 l/min and renal plasma clearance 0.22 l/kg. The formation of OH-TA-ester was very rapid and the concentration of the metabolite exceeded that of TA at all times. After i.v. administration the urinary recovery of TA and OH-TA-ester was 4.4% and 50.9%, respectively. The bioavailability of TA was 52%, corresponding to absorption of 83%. TA is partly eliminated by a first-pass-effect. The main metabolite of TA is OH-TA-ester, which is pharmacologically active.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00543797
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  • 70
    Electronic Resource
    Electronic Resource
    On the pharmacokinetics of pengitoxin and its cardioactive derivative 16-acetyl-gitoxin (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 369-373 
    Details
    ISSN: 1432-1041
    Keywords: pengitoxin ; pharmacokinetics ; 16-acetylgitoxin ; absorption ; urinary excretion ; healthy subjects ; cardiac glycoside
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of pengitoxin has been studied in 28 healthy subjects after intravenous and oral administration. The mean plasma concentration 24 h after 0.5 mg i.v. was 5.2 ng · ml−1. Following an open two-compartment model a mean elimination half-life of 60.5 h (24.9 to 103.5 h) and a mean volume of distribution (Vdarea) of 66.91 (31.8 to 109.61) were calculated. Absorption calculated by comparison of the AUC0-∞-values amounted to 99%. Within 4 days, 16.7% (11.7 to 21.1%) or 27.8% (18.4 to 33.7%) (0.5 mg i.v. or 1.2 mg p.o.) was excreted in urine. After pengitoxin 0.5 mg i.v. total body clearance and renal clearance were 13.3 ml · min−1 (7.0 to 18.6 ml · min−1) and 3.0 ml · min−1 (1.9 to 3.9 ml · min−1) respectively. The elimination half-life of pengitoxin is longer than that of digoxin and distinctly shorter than that of digitoxin, whilst its distribution volume and clearance are closer to those of digitoxin than of digoxin.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01037950
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  • 71
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    Volume of distribution terms for a drug (ceftriaxone) exhibiting concentration-dependent protein binding I. Theoretical considerations (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 399-405 
    Details
    ISSN: 1432-1041
    Keywords: ceftriaxone ; pharmacokinetics ; concentration-dependent binding ; volume of distribution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have theoretically examined the influence of plasma protein binding (specifically the fraction unbound, fp) on the pharmacokinetic parameters following rapid injection of a drug undergoing concentration-dependent binding. Particular emphasis was placed on the apparent volume of distribution terms based on both total and unbound drug concentrations. Computer simulations were performed to establish the validity and utility of such relationships. The following observations were made: a) distributional parameters based on total drug (both Vβ and the model-independent VSS) were inaccurate/invalid; b) V β based on unbound drug was misleading; c) the model-independent VSS for unbound drug accurately predicted the steady state situation. Furthermore, two new terms ( $$\bar f_P $$ and $$\bar V_{SS}^T $$ ) were introduced which provide additional insight concerning the disposition of this type of drug. The $$\bar f_P $$ is the area-weighted average fraction unbound in the plasma and $$\bar V_{SS}^T $$ is the corrected steady state distribution term for total drug levels. The present study indicates that useful distributional and clearance terms can be calculated for this type of drug, provided that the time course of unbound drug as well as total drug can be followed. Moreover, guidelines for their extrapolation to steady state conditions and their correct interpretations are discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01037955
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  • 72
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    Electronic Resource
    Rapid achievement of a serum concentration plateau of digoxin through controlled infusion (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 455-457 
    Details
    ISSN: 1432-1041
    Keywords: digoxin ; concentration plateau ; pharmacokinetics ; systolic time intervals ; optimal infusion scheme ; dose-response data
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Using a volume-controlled infusion pump, a mean serum plateau level of digoxin of 4–5 ng/ml was rapidly achieved and maintained in 6 healthy volunteers. The infusion scheme was calculated on the basis of data published on the pharmacokinetics and pharmacodynamics of digoxin following bolus intravenous injection. The magnitude of the response (change in electromechanical systole) at the end of the plateau phase was comparable to that observed with the concentration in the therapeutic range at steady state.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542110
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  • 73
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    Electronic Resource
    Pharmacokinetics of canrenone after oral administration of spironolactone and intravenous injection of canrenoate-K in healthy man (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 449-453 
    Details
    ISSN: 1432-1041
    Keywords: canrenone ; pharmacokinetics ; plasma level ; bioavailability ; urinary excretion ; spironolactone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five healthy male volunteers received canrenoate-K 200 mg (Sincomen® pro injectione) by intravenous injection and one week later spironolactone 200 mg (Sincomen®-100) orally. Plasma levels and urinary excretion of unchanged canrenone were determined up to 24 h by a specific HPLC method. Following intravenous administration, the maximum plasma level of 2066±876 ng/ml was found after 29±15 min and thereafter the concentration declined with a half-life of 3.7±1.2 h. Total clearance was 4.2±1.7 ml/min·kg. After oral ingestion, the maximum concentration of 177±33 ng/ml was observed at 4.4±0.9 h. The absolute bioavailability of canrenone was 25±9%. Within 24 h, respectively 0.4 and 0.6 mg, canrenone were excreted by the kidney after intravenous and oral administration. The half-life of elimination was 4.9±1.8 h (i.v.) and 3.9±1.2 h (p.o.).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542109
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  • 74
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    Electronic Resource
    Pharmacokinetics of methadone in methadone maintenance treatment: Characterization of therapeutic failures (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 497-501 
    Details
    ISSN: 1432-1041
    Keywords: methadone ; pharmacokinetics ; steady state ; addiction rehabilitation ; therapeutic failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Deuterated methadone (M-d3) and GC-MS analysis were used to study the steady state pharmacokinetics of methadone (M) in eight patients reported as therapeutic failures in a methadone maintenance treatment programme. The patients were compared to an unselected group of 12 patients stabilized on M for 25 days. During one dosage interval a pulse dose of M-d3 was administered intravenously instead of the oral M-dose (M-d0). The pharmacokinetic parameters, half-life in the β-phase (t1/2β), volume of distribution during the postdistributive phase (Vdβ) and during steady state (Vdss) were determined as well as the body (ClS) and renal (ClR) clearances of M. Pronounced differences in Vdβ and Vdss were found between the two groups. The therapeutic failures had a smaller Vdβ and Vdss 3.09±0.96 l/kg and 2.74±0.96 l/kg vs 4.56±1.00 l/kg and 4.20±0.78 l/kg in the control group. The differences were due to changes between the groups in the volume of the central compartment. Differences between the groups were also found in t1/2β — 24.5±2.6 h in the therapeutic failures and 34.0±7.0 h (p〈0.001) in the comparison group. However, the change in t1/2β was probably a consequence of the change in Vdβ, as the body clearance of M was similar in the two groups — 104±36 ml/min vs 111±36 ml/min. The smaller volume of distribution could lead to unacceptably high fluctuation of M in the central compartment, and withdrawal symptoms during the latter part of the dosage interval. The appropriate treatment of this subgroup of patients on methadone treatment is not to increase the dose but to shorten the dosage interval. Alternatively, a longer-acting opiate, such as 1-α-acetylmethadol (LAAM), may be used.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542117
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  • 75
    Electronic Resource
    Electronic Resource
    Pharmacodynamic and pharmacokinetic study of oral and intravenous penbutolol (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 529-534 
    Details
    ISSN: 1432-1041
    Keywords: penbutolol ; pharmacokinetics ; blood pressure effect ; heart rate effect ; dose response relationship ; tolerance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The present study was done to establish the dose-response relationships for effects on heart rate and systolic and diastolic blood pressure, tolerance and plasma disappearance kinetics after large intravenous and oral doses of penbutolol. Twelve healthy volunteers were randomly allocated to receive penbutolol (n=8) or placebo (n=4) in this single blind, placebo-controlled investigation. The degree of beta-blockade was measured by standarized exercise tests at work loads selected to produce a heart rate of 150/min without treatment. Penbutolol was given as single i.v. doses of 3, 6 and 12 mg and as 40, 80 and 120 mg once daily for one week, measurements being made 2 and 24 h after the last dose. Penbutolol i.v. did not influence the resting heart rate but it did reduce resting systolic blood pressure in a non-dose dependent manner. Exercise heart rate and systolic pressure were lowered by all the intravenous doses. All oral doses of penbutolol lowered exercise heart rate and systolic blood pressure to the same extent. The reductions in exercise tachycardia was still present after 24 h. After i.v. administration t1/2 was approximately 1.2 h and the volume of distribution was 32–42 l. All doses were well tolerated.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542123
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  • 76
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    Electronic Resource
    Relationships between several pharmacokinetic parameters and psychometric indices of subjective effects of Δ9-tetrahydrocannabinol in man (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 633-637 
    Details
    ISSN: 1432-1041
    Keywords: delta-9-tetrahydrocannabinol ; mood ratings ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary This study explored the relationships in man between various pharmacological effect of Δ9-tetrahydrocannabinol (THC), plasma THC concentration, and pharmacokinetic parameters of THC. Three male and three female experienced marihuana users smoked two standard marihuana cigarettes. The relationships between heart rate, subjective “high” rating, Linear Mood Scale factors, and plasma THC concentration were assessed. Significant correlations were observed between various Linear Mood Scale factors and pharmacokinetic parameters reflecting the magnitude of drug intake and the degree of temporal dissociation between the time courses of plasma THC concentration and pharmacological effects (tachycardiac effect, “high”). In particular, the disturbed/weird and sensitive/aware mood factors correlated positively with pharmacokinetic measures of drug intake and time lag to effect. A more reliable index of intoxication with THC may be provided by the global subjective “high” rating, rather than other ratings more specific for particular moods.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542351
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  • 77
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of digoxin in pregnancy (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 117-121 
    Details
    ISSN: 1432-1041
    Keywords: serum digoxin ; pregnancy ; digoxin-renal-clearance ; creatinine-clearance ; digoxin-elimination ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Digoxin-renal-clearance, creatinine-clearance, 24-h urine elimination of digoxin and serum digoxin were studied in 15 patients in the third trimester of pregnancy and 6 to 12 weeks post-partum. There was significant fall post-partum in the first three. There was also a significant fall post-partum in serum digoxin levels. This finding was unexpected, but may be due to heightened absorption exceeding increased elimination because of the physiological status in pregnancy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00544027
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  • 78
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of theophylline in Ethiopian children of differing nutritional status (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 89-92 
    Details
    ISSN: 1432-1041
    Keywords: theophylline ; kwashiorkor ; marasmus ; children ; nutritional status ; pharmacokinetics ; dosage recommendation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of theophylline in Ethiopian children of differing nutritional status was studied. In 8 children of normal weight, the t1/2β (4.93 h) plasma clearance (1.22 ml/min/kg and Vd area (504 ml/kg) were similar to those of Swedish children of normal weight. In children with marasmus or kwashiorkor there was an increased volume of distribution. The increase in Vd was reflected in an increased biological half-life, in spite of a slight but not significant increase in clearance in both of these groups of children. The pharmacokinetic changes in clearance and volume of distribution found in malnutrition should counteract each other, so from a clinical point of view theophylline can be given to Ethiopian children according to the standard dosage recommendation, regardless of nutritional status.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00613932
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  • 79
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    Electronic Resource
    Bioavailability and pharmacokinetics of theophylline in plain uncoated and sustained-release dosage forms in relation to smoking habit I. Single dose study (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 79-87 
    Details
    ISSN: 1432-1041
    Keywords: theophylline ; smoking habit ; absolute bioavailability ; pharmacokinetics ; sustained release preparation ; plain tablet preparation ; antipyrine pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The bioavailability and pharmacokinetics of theophylline from a plain uncoated and 2 newly designed, sustained-release tablet formulations, as compared to intravenous aminophylline, were studied in 12 healthy adult male volunteers. The subjects were divided into two groups (n=6) with respect to smoking habit and on 4 separate occasions each received, on a randomized cross-over basis, a single dose of 400 mg equivalent of theophylline from every dosage form. The intravenous aminophylline study showed that habitual smoking had a significant (p〈0.05) effect on plasma theophylline clearance (0.051±0.006 vs 0.035±0.004 l/kg/h). Smoking significantly reduced the raw AUC from the 4 dosage forms (p〈0.05), but did not change the characteristics of absorption of each formulation. There was a non-significant trend towards reduced absolute bioavailability of theophylline from sustained-release formulations in smokers (percentage mean difference — 16% for one formulation and 13% for another). The trend was not observed for the plain uncoated tablet, which was rapidly absorbed (p〈0.01 to 0.05 in Ka, tmax and Cmax compared to sustained-release tablets). Similarity of the in vitro dissolution profiles of the two sustained-release formulations did not imply similarity of the in vivo absorption characteristics. Plasma clearances of theophylline and antipyrine were significantly correlated (p〈0.05,r=0.693,n=10). Thus, smoking enhanced the elimination of theophylline regardless of the dosage form administered. However, the extent to which habitual smoking may affect the hepatic first-pass effect on theophylline from sustained-release formulations requires further study. The results also suggest that theophylline and antipyrine may share a similar or common and presumably polycyclic hydrocarbon-inducible form(s) of microsomal drugmetabolizing enzyme.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00613931
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  • 80
    Electronic Resource
    Electronic Resource
    Bioavailability of oral dexamethasone during high dose steroid therapy in neurological patients (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 103-108 
    Details
    ISSN: 1432-1041
    Keywords: dexamethasone ; bioavailability ; pharmacokinetics ; ‘first-pass’ effect ; pre-systemic elimination
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and oral biovailability of dexamethasone were studied in 6 patients with neurological disease being treated with high dosages of the drug. A specific high performance liquid chromatographic assay was used to measure dexamethasone concentrations. Unlike the previously published mean figure of 0.78 for the oral bioavailability of the drug given in single doses to healthy volunteers, the mean bioavailability of dexamethasone in the patients studied was 0.53±SD 0.40. It appeared more likely that this incomplete bioavailability was due to presystemic elimination than to poor absorption. The intravenous clearance of the drug was relatively high (0.4902±SD 2291 l kg−1, approximately 65% of expected hepatic plasma flow), the oral clearance higher (2.5804±SD 3.2181 l kg−1 h−1) while the absorption rate constant (4.8729±8.4998 h−1), suggested rapid absorption after oral administration. Prior phenytoin and possibly prior dexamethasone therapy is likely to have contributed to the higher clearance values of the drug in these patients than the values reported in healthy volunteers after single dose studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00613935
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  • 81
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    Electronic Resource
    Elimination of cefroxadine (CGP-9000) from patients undergoing dialysis (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 109-112 
    Details
    ISSN: 1432-1041
    Keywords: cefroxadine ; haemodialysis ; pharmacokinetics ; terminal renal impairment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of cefroxadine was studied in 17 patients with terminal renal impairment, 10 of whom were undergoing 5 h dialysis sessions. The antibiotic was administered as a single oral dose of 500 mg. Cefroxadine followed a single compartment open kinetic model. During the interdialysis period in patients with terminal renal impairment, an average Cmax of 26.59 µg/ml and a tmax of 3.65 h were reached, which are greater than in patients with normal renal function. The serum half-life was reduced from 23.55 h in the interdialysis periods to 3.40 h during the dialysis sessions. The average extraction coefficient was 0.249. It is recommended that a 500 mg dose cefroxadine should be administered at the end of each dialysis session if the interdialysis period is 48 h.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00613936
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  • 82
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    Pharmacokinetics of levonorgestrel in Indian women (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 255-259 
    Details
    ISSN: 1432-1041
    Keywords: levonorgestrel ; nutritional status ; combination pill ; pharmacokinetics ; indian women
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A low dose combination pill containing levonorgestrel 150 µg and ethynylestradiol 50 µg was administered orally to 13 women. Based on their anthropometric index they were classed as well-nourished (Group A) or undernourished (Group B). Plasma levels of levonorgestrel at various intervals after dosing were analysed by a specific radioimmunoassay and its pharmacokinetic parameters were computed. Peak plasma levels in both groups occurred within 2 h and the absorption half-lives were also similar. The decline in plasma levonorgestrel showed a tri-exponential decline in all Group A women, whereas it was biphasic in most of Group B. The π t1/2 was lower in Group A women and the α-phase was found to be negligible in Group B. A significant positive correlation between elimination half-life (β t1/2) and some of the anthropometric indices suggests a possible role of nutritional status in the metabolic handling of levonorgestrel.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00613828
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  • 83
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    Doxorubicin and 5-fluorouracil plasma concentrations and detectability in parotid saliva (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 261-266 
    Details
    ISSN: 1432-1041
    Keywords: doxorubicin ; 5-fluorouracil ; pharmacokinetics ; parotid saliva ; plasma concentration ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Doxorubicin and 5-fluorouracil pharmacokinetics were studied in 19 volunteers with various advanced neoplastic diseases who received 50–90 mg doxorubicin or 600–1000 mg 5-fluorouracil intravenously, followed by plasma and parotid saliva collection over a 75 min period. The extent to which these chemotherapeutic agents are bound to plasma proteins, at concentrations chosen to approximate plasma concentrations, was measured by equilibrium dialysis. Both agents were quantitated by high-performance liquid chromatography. As reported previously, a wide range of plasma levels were found among patients receiving similar doses of either doxorubicin or 5-fluorouracil. It appears that in addition to being quickly cleared from the plasma both chemotherapeutic agents are excreted in detectable amounts in parotid saliva, a route of elimination heretofore given little or no attention. Excretion in the saliva exposes the mucosa of the upper gastrointestinal tract to 5-fluorouracil after intravenous administration and may play a part in causing stomatitis in patients receiving it by this route. Since there are huge interindividual and pronounced intraindividual differences in S/P ratios mostly not systematically related to the drugs' concentration in plasma, the concentration in parotid saliva was not useful in predicting the level of free doxorubicin or 5-fluorouracil in plasma.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00613829
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  • 84
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    Electronic Resource
    The pharmacokinetics of melphalan in patients with multiple myeloma: An intravenous/oral study using a conventional dose regimen (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 283-285 
    Details
    ISSN: 1432-1041
    Keywords: melphalan ; myeloma ; pharmacokinetics ; i.v. dosing ; oral dosing
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of melphalan have been studied after intravenous and oral dosing (10 mg) in 6 patients with multiple myeloma. After intravenous administration, mean plasma t0.5α was 8.0±2.3 min, t0,5β was 63.3±8.7 min, and total systemic clearance was 510.4±57.9 ml/min. After oral administration, the drug was rapidly absorbed (lagtime=18.4±3.7 min, absorption rate constant=0.0547±0.0166 min−1, Tmax=59.3±6.6 min), but there was considerable variation in its bioavailability (61.5−102.0% mean 78.3±6.3%). Variability in drug absorption may be responsible, at least in part, for variation in response to this drug.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00613833
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  • 85
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    Electronic Resource
    Pharmacokinetics of oxmetidine, a new histamine H2-receptor antagonist, after single oral and intravenous doses (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 353-356 
    Details
    ISSN: 1432-1041
    Keywords: oxmetidine ; pharmacokinetics ; bioavailability ; plasma half-life ; clearance ; oral dose ; i.v. dose
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentration curves and urinary excretion of oxmetidine after administration of single i.v. (100 mg) and oral (200 mg) doses have been studied in 11 patients with peptic ulcer disease. The mean bioavailability of the drug was 70% (range 53–91%). After intravenous administration, the mean plasmat 1/2β was 3.0 h, the mean apparent volume of distribution 0.7 l/kg, the mean total plasma clearance 12.3 l/h and the mean plasma renal clearance was 0.7 l/h. Following intravenous and oral administration an average of 6% and 3%, respectively, of unchanged drug was found in the urine. The plasma concentration curve after oral administration in most patients exhibited two maxima, with peak concentrations appearing between 45 and 210 min after dosing.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00610054
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  • 86
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    Electronic Resource
    Analytical model of some pharmacokinetic and pharmacodynamic properties of fazadinium in man (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 407-413 
    Details
    ISSN: 1432-1041
    Keywords: neuromuscular blockade ; fazadinium ; pharmacokinetics ; pharmacodynamics ; predictive model ; receptor occupation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The neuromuscular blocking characteristics and plasma concentration decay of fazadinium bromide, a short acting, non-depolarizing muscular relaxant, were simultaneously observed under standardised conditions in 6 healthy, anaesthetized, adult patients. The results were analyzed by a new pharmacodynamic model, which takes into account certain relationships describing the binding of non-depolarizing neuromuscular blocking agents and the postsynaptic receptor occupation ratio. According to the simulations performed, the pharmacodynamic parameters determined: KB-apparent value of equilibrium constant of fazadinium — receptors exchange (mean ± SEM) 0.404+0.045 µmol/l, and the value of postsynaptic occupation ratio for 50% paralysis of 0.89±0.004 were in agreement with values reported in the literature for mammalian neuromuscular junctions in vitro. The apparent validity of the pharmacodynamic model and its value in simulating dose/effect relationships of non-depolarizing neuromuscular blocking agents are discussed and illustrated.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00610063
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  • 87
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    Electronic Resource
    Pharmacokinetics of bredinin in renal transplant patients (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 457-461 
    Details
    ISSN: 1432-1041
    Keywords: bredinin ; immunosupressive agent ; pharmacokinetics ; renal transplant patients ; renal function ; absorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A pharmacokinetic study of bredinin, a new immunosupressive agent, was carried out in 28 renal transplant patients. Serum bredinin concentration-time curves were analyzed using a one-compartment open model with a first order absorption process. The peak serum bredinin level appeared 2.4 h after oral administration of bredinin 50–200 mg. The calculated mean peak serum level was 0.852 µg/ml/mg/kg, when the dose was adjusted to the body weight of the patient. In the dosage range used of 0.85–4.46 mg/kg, a linear relationship was observed between the dose and the peak serum bredinin level. The elimination rate of bredinin from serum was dependent on kidney function, and the elimination rate constant was well correlated with the endogenous creatinine clearance. No circadian rhythm was apparent in the elimination rate constant. The absorption rate of bredinin from the gastrointestinal (GI) tract was affected by GI diseases. The need for dosage adjustment based on the renal function of the transplant patient is suggested.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609886
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  • 88
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of tocainide in patients with renal dysfunction and during haemodialysis (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 503-507 
    Details
    ISSN: 1432-1041
    Keywords: tocainide ; pharmacokinetics ; renal failure ; antiarrhythmic drug ; haemodialysis ; cirrhosis ; acetyldigoxin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition of tocainide was studied in 15 patients with renal dysfunction. In 9 with total renal failure, the plasma half-life ranged from 16.6 to 42.7 h and total plasma clearance from 35 to 94 ml/min. The longest half-lives were found in 1 patient with cirrhosis, 3 taking the enzyme inhibitor allopurinol, and 1 on cimetidine. The mean half-life in the remaining patients was 22.3±4.8 h (±SD). During a 4 h haemodialysis, the half-life in the 9 patients decreased to 8.5±4.6 h, which was calculated to correspond to removal of 25±14% of the drug from the body. In 6 patients with impaired renal function (creatinine clearance 10–55 ml/min) the tocainide half-life ranged from 13.2 to 22.0 h and total plasma clearance from 72 to 122 ml/min. One patient was taking allopurinol and 1 dihydralazine, and the mean half-life in the others was 19.2±4.0 h. The apparent volume of distribution was similar to that found previously in healthy subjects. The results suggest that tocainide elimination is predictably reduced in patients with renal disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609893
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  • 89
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of prenalterol after single and multiple administration of controlled release tablets to patients with congestive heart failure (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 495-502 
    Details
    ISSN: 1432-1041
    Keywords: prenalterol ; pharmacokinetics ; food ; congestive heart failure ; plasma levels ; urinary excretion ; metabolites
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of prenalterol, a partial β-adrenoceptor agonist, has been studied in 12 patients with congestive heart failure, following single and repeated oral doses of 40 mg b.i.d. as controlled release tablets. A tracer dose of3H-labelled drug was given i.v. on 2 occasions to establish the variability of the pharmacokinetic parameters. Plasma levels and urinary excretion of prenalterol were measured after the oral and intravenous doses, and in addition, total radioactive metabolites were determined after the i.v. administration. Only small differences in the pharmacokinetics were observed when the i.v. tracer dose was given with the single oral dose or with the oral maintenance dose at steady state. The mean plasma elimination half-life was 2.4 h, the apparent volume of distribution 2.61/kg and the total body clearance about 800 ml/min. About 90% of the dose was excreted in urine, of which 30% was the parent drug. The remaining fraction comprised three metabolites, which were quantified by HPLC. Plasma levels of prenalterol close to steady state were obtained within 2 days and were maintained on a b.i.d. dosage regimen with controlled release tablets. The levels were independent of whether the tablets were taken fasting or with a standardized light meal. An average of 14% of the oral dose was recovered as prenalterol in urine after a single dose and 16% after a maintenance dose at steady state. Thus, about 45–55% of prenalterol reached the systemic circulation. The pharmacokinetic parameters in patients with congestive heart failure differed slightly from those in healthy subjects, but not sufficiently to require a change in the oral dosage regimen.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609892
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  • 90
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of gentamicin in very low birth weight preterm infants (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 649-653 
    Details
    ISSN: 1432-1041
    Keywords: gentamicin ; preterm infants ; pharmacokinetics ; low birth weight ; dosage regimens
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Low birth weight preterm infants with suspected infection were administered gentamicin intramuscularly every 18 h (2.5 mg/kg) or 24 h (3.0 mg/kg). For both dosage regimens plasma gentamicin levels were monitored during a dosage interval on three separate occasions over a 10 day period. Both regimens gave satisfactory plasma concentrations and there was no important statistically significant difference between the two. The body clearance of gentamicin correlated with gestational age (r=0.76, p〈0.01). The results indicate either regimen may be useful in the clinical situation but from a practical standpoint administration every 24 h may be easier to comply with then every 18 h.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542216
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  • 91
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    Electronic Resource
    Systemic availability of acetylsalicylic acid in normal men and women and its effect on in vitro platelet aggregability (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 679-682 
    Details
    ISSN: 1432-1041
    Keywords: acetylsalicylic acid ; salicylic acid ; platelets ; pharmacokinetics ; sex difference ; platelet aggregation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The systemic availability of acetylsalicylic acid (ASA) after oral ingestion of 1 g in an effervescent formulation was 16.3±2.0% and 16.9±3.2% of the ingested dose in normal women and men, respectively. The average plasma half-life of ASA in each sex was also identical at 18.5±1.4 and 18.1±1.2 min, respectively. The inhibitory effect of ASA on collagen-induced platelet aggregation in vitro on blood from both sexes was studied. The IC50 was 23.9±2.9 µg/ml in females and 22.5±2.7 µg/ml in males, which did not differ significantly. The inhibition by salicylic acid (SA) of the antiaggregatory effect of ASA was similar in both sexes with increases in IC50 to 33.5±5.1 µg/ml in females (p〈0.02) and to 29.5±3.8 µg/ml in males (p〈0.05). It is concluded that the observed sex-difference in the antithrombotic effect of ASA cannot be explained neither by differences between females and males in the pharmacokinetic properties of ASA after oral ingestion, nor by differences in the in vitro effect of ASA on the platelet aggregation induced by collagen.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542222
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  • 92
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    Electronic Resource
    Aspirin pharmacokinetics in migraine. The effect of metoclopramide (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 777-785 
    Details
    ISSN: 1432-1041
    Keywords: aspirin ; migraine ; salicylic acid ; metoclopramide ; drug absorption ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of aspirin (ASA) in acute migraine attacks, and the influence of metoclopramide on ASA disposition, were studied in 32 attacks in 30 patients. An intergroup comparison was made between normal volunteers, and the migraineurs, who were assigned at random to one of three treatment groups: a) oral ASA only (900 mg); b) 10 mg oral metoclopramide + oral ASA 900 mg; c) 10 mg i. m. metoclopramide + oral ASA 900 mg. Plasma ASA and SA levels were measured serially over 2 h, and the resultant data evaluated pharmacokinetically. Metoclopramide plasma levels were also determined over 2 h, and the results compared with a second group of normal volunteers. The rates of oral ASA absorption and elimination were unaffected by migraine. Mean absorption rate constants of 14.15±9.48 h−1 (normals), 7.91±3.42 h−1 (ASA only), 6.74±3.26 h−1 (ASA + oral metoclopramide) and 8.12±2.82 h−1 (ASA + i. m. metoclopramide) were calculated. Mean elimination rate constants ranged from 2.56 h−1 to 3.37 h−1, and did not differ significantly between controls and migrainous patients. Values for absorption lag time, however, were higher in migraine patients treated with ASA alone than in any other group. The amount of ASA absorbed unhydrolysed was also lower in this group. SA levels appeared unaffected either by the migraine attack, or by metoclopramide administration, over the period of study. Metoclopramide plasma levels were significantly lower during migraine attacks, and the amount of drug absorbed up to 2 h from dosing was also reduced, as compared with non-migrainous subjects. It was concluded that acute migraine caused a delay in orally administered ASA reaching its absorption sites, probably as a result of gastric stasis, and may have decreased the amount of ASA absorbed. The prior administration of metoclopramide, either orally or intramuscularly, reduced the absorption lag time, and thus promoted the early absorption of ASA, probably by restoring alimentary tract motility.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00607087
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  • 93
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    Electronic Resource
    Chloramphenicol pharmacokinetics in Ethiopian children of differing nutritional status (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 819-823 
    Details
    ISSN: 1432-1041
    Keywords: chloramphenicol ; children ; pharmacokinetics ; oral dose ; absorption ; i.v. dose ; kwashiorkor ; marasmus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of i.v. chloramphenicol succinate and oral chloramphenicol palmitate were studied in Ethiopian children with different nutritional states. In children with kwashiorkor the plasma clearance of chloramphenicol was significantly lower than in children of normal weight (4.16 ml/min/kg versus 7.53 ml/min/kg). In consequence the mean half-life was prolonged (3.76 h versus 2.85 h) and this led to somewhat higher plasma levels in the kwashiorkor children. The influence of the pathophysiological changes offset one another so that plasma concentrations within the therapeutic range were obtained in children with kwashiorkor given recommended standard i.v. doses. The absorption of chloramphenicol after oral administration in severely malnourished children was erratic, which suggests that this route should be avoided in such patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00607094
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  • 94
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    Electronic Resource
    Tizanidine — Initial pharmacokinetic studies in patients with spasticity (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 65-67 
    Details
    ISSN: 1432-1041
    Keywords: tizanidine ; pharmacokinetics ; spasticity ; multiple sclerosis ; haematological parameters ; electromyogram
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The time-course of plasma concentrations of the antispasticity agent tizanidine were measured by a specific radioimmune-assay in six adults who had severe spasticity due to multiple sclerosis. The drug was given as a single oral 4 mg dose to each subject. The drug had a mean absorption half-life of 0.30±0.155 h following a mean lagtime of 0.361±0.118 h, and a mean terminal elimination half-life of 4.16±2.06 h. Only 2.65±0.82% of the dose was excreted unchanged in urine in 2 h. Calculated values of clearance and apparent volume of distribution were almost certainly overestimates as it seems probable that the orally-administered drug undergoes significant presystemic elimination (its bioavailability was not determined in the investigation here reported). Relief of spasticity, from the dosage used, was relatively slight and appeared greatest at the time of peak plasma levels of the drug.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00544016
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  • 95
    Electronic Resource
    Electronic Resource
    Effect of ethanol intake on disopyramide elimination by healthy volunteers (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 103-105 
    Details
    ISSN: 1432-1041
    Keywords: disopyramide ; ethanol ; pharmacokinetics ; interaction ; metabolic clearance ; renal clearance ; diuresis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of ethanol intake on disopyramide elimination was examined in an open cross-over study in six healthy volunteers. No effect of ethanol on the elimination half-life or total body clearance of disopyramide was found, although it did decrease the percentage of mono-N-dealkylated disopyramide excreted in the urine (p〈0.05) as well as the relative metabolic clearance of disopyramide (p〈0.05). The renal clearance of disopyramide was increased by 19±16% (p〈0.05) in subjects in whom ethanol caused a diuresis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00544024
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  • 96
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    Electronic Resource
    Cimetidine disposition in patients with Laennec's cirrhosis during multiple dosing therapy (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 223-229 
    Details
    ISSN: 1432-1041
    Keywords: cimetidine ; alcoholic cirrhosis ; multiple dosing ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition of cimetidine after oral and intravenous administration during multiple dosing was studied in 11 patients with Laennec's cirrhosis. The average metabolic clearance of cimetidine in these patients was 151/h, similar to values reported for normal subjects. However, in 4 subjects with plasma prothrombin times above normal, the metabolic clearance was significantly decreased and ranged between 4.3 and 13.01/h. The renal clearance of cimetidine was proportional to the creatinine clearance in all subjects, regardless of the severity of the liver disease. The clearance of cimetidine in patients with Laennec's cirrhosis, therefore, appears to be predictabable from creatinine clearance and prothrombin time.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00543795
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  • 97
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    Electronic Resource
    CSF penetration and pharmacokinetics of midazolam (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 247-251 
    Details
    ISSN: 1432-1041
    Keywords: midazolam ; CSF penetration ; pharmacokinetics ; benzodiazepines
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The passage of midazolam, a new benzodiazepine derivative with highly water-soluble salts, into cerebrospinal fluid (CSF) was studied after a single oral dose of 15 mg (n=23), a single i.m. injection of 0.075 or 0.150 mg/kg (n=8), or a single i.v. dose of 0.075 mg/kg (n=26). Contrary to previous studies of diazepam and flunitrazepam, the rapid clinical effect of midazolam cannot be explained by rapid passage into human lumbar CSF. In only four cases following intravenous injection was there a measurable amount of drug in lumbar CSF (lower limit of assay sensitivity=2 ng/ml). After both oral (n=10) and intramuscular (n=8) administration, midazolam was rapidly absorbed, with attainment of the peak serum level after about 0.5 h. The pharmacokinetic parameters following i.v. injection of midazolam (n=6) explain its rapid but brief duration of action.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00543799
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  • 98
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    Electronic Resource
    Erythromycin absorption in healthy volunteers from single and multiple doses of enteric-coated pellets and tablets (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 271-273 
    Details
    ISSN: 1432-1041
    Keywords: erythromycin ; tablets absorption ; enteric-coated pellets ; blood concentrations ; healthy volunteers ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absorption of erythromycin from two different enteric-coated preparations was evaluated in three groups of healthy volunteers. After a single dose, taken after an overnight fast, absorption was significantly better from enteric-coated pellets than from tablets; both the mean peak serum concentration and the peak mean level were higher (p〈0.01) in all three groups, and the mean area under the serum concentration-time curve (AUC) was at least 65% larger. Eight out of 23 subjects showed no or only a very low serum concentration after the enteric-coated tablets. In a follow-up study, 250 mg doses were given 6-hourly for 3 days, and again the mean maximum serum concentration was significantly higher (p〈0.05) after the pellets. In conclusion, enteric-coated pellets led to more regular and predictable absorption of erythromycin than did coated tablets.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00543802
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  • 99
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    Electronic Resource
    Pharmacokinetics of pindolol in Kenyan Africans (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 425-426 
    Details
    ISSN: 1432-1041
    Keywords: pindolol ; Africans ; pharmacokinetics ; single dose
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of pindolol was studied in 8 normal Africans following administration of a single oral 10 mg dose. The mean peak concentration was 30.2±5.0 ng·ml−1, the mean half-life (t1/2) of the elimination phase was 3.4±1.1 h, and the total body clearance was 628±13 ml·min−1. The apparent volume of distribution was 3.0±1.3 l·kg−1. The values are the same as those reported in Europeans.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01037959
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  • 100
    Electronic Resource
    Electronic Resource
    Chronic propranolol administration during pregnancy (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 481-490 
    Details
    ISSN: 1432-1041
    Keywords: propranolol ; pharmacokinetics ; pregnancy ; hypertension ; naphthoxylactic acid
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of propranolol (P) and its major metabolites, propranolol glucuronide (PGLUC), 4-hydroxypropranolol (4OHP), 4-hydroxypropranolol glucuronide (4OHPGLUC) and naphthoxylactic acid (NLA), (Walle et al. 1972) were determined, whenever possible, in the first, second and third trimesters of pregnancy in thirteen patients and also when these patients were at least three months post-partum. No correlations were found between the mean arterial blood pressure (post-therapy) or the fall in blood pressure as a result of the P therapy (p〉 〉0.05) and P dose, peak P plasma concentrations, peak 4-hydroxypropranolol (4OHP) plasma concentrations or peak (P plus 4OHP) plasma concentrations. However, a positive nonlinear relationship was found between the daily P dose (independent variable) and peak P plasma concentrations over the daily dose range 30–160 mg/day. The elimination half-lives of NLA for patients in the third trimester of pregnancy were significantly shorter (p=0.072, df=13) than those when the patients were at least three months post-partum. Also, the areas under the plasma level-time curves of NLA were significantly less (p〈0.05, df=13) for patients in the third trimester of pregnancy than when these patients were at least three months post-partum. The results of this study indicate that the pharmacokinetics of P, PGLUC, 4OHP and 4OHPGLUC are not significantly altered by pregnancy. However, the kinetics of NLA do appear to be altered. The formation of NLA by N-dealkylation of P and further oxidation, appears to be competitively inhibited by unidentified substances, perhaps endogenous steroids, especially in the third trimester when compared to at least three months post-partum.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542115
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