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  • Electronic Resource  (599)
  • 1985-1989  (599)
  • pharmacokinetics  (599)
  • 201
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and pharmacodynamics of controlled-release metoprolol: A comparison with atenolol (1988)
    Springer
    European journal of clinical pharmacology 33 (1988), S. S19 
    Details
    ISSN: 1432-1041
    Keywords: atenolol ; controlled-release metoprolol ; pharmacokinetics ; exercise heart rate ; exercise systolic blood pressure ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Pharmacokinetic and pharmacodynamic properties of a new controlled-release (CR) formulation of metoprolol1 have been compared with those of atenolol2. Metoprolol CR (100 mg and 200 mg), atenolol (50 mg and 100 mg) and placebo were each given once daily for four days in a double-blind, cross-over study to ten healthy men. The plasma concentration-time profiles were more even with metoprolol CR than with atenolol over the 24-h dose interval, shown by the lower fluctuation ratio and the longer time period during which the plasma concentration exceeded 50% of the maximum concentration. All four active treatment regimens reduced exercise heart rate over the 24-h period compared with placebo. However, the reduction in both exercise heart rate and systolic blood pressure (SBP) was more even with metoprolol CR than with atenolol. The remaining β1-blockade after 24 h, expressed as the percentage reduction in exercise heart rate in relation to placebo, was significantly greater after the administration of metoprolol CR, 200 mg, than after either dose of atenolol. At this time the β1-blockade with metoprolol CR, 100 mg, was similar to that with atenolol, 100 mg. At peak plasma concentrations, 4 h after the dose, the subjects experienced less fatigue during exercise with metoprolol CR than with atenolol.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00578408
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  • 202
    Electronic Resource
    Electronic Resource
    Drug treatment and prevention of malaria (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 1-14 
    Details
    ISSN: 1432-1041
    Keywords: malaria ; Arbor febrifuga (cinchona tree) ; Plasmodium spec. ; Artemesia annua (Qinghao) ; antimalarial drugs ; pharmacokinetics ; toxicity ; treatment ; prophylaxis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01061409
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  • 203
    Electronic Resource
    Electronic Resource
    Effect of a single daily dose treatment of fenofibrate on plasma lipoproteins in hyperlipoproteinaemia IIb (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 25-28 
    Details
    ISSN: 1432-1041
    Keywords: hyperlipoproteinaemia ; fenofibrate ; single daily dose ; plasma lipids ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The safety and efficacy of a single daily dose of fenofibrate (200 mg) have been evaluated in 12 Type IIB hyperlipidaemic patients in a three-month study. At the same time the pharmacokinetics was studied to check whether this new dosage schedule would give a therapeutic plasma levels of fenofibrate. At the single daily dose of 200 mg, fenofibrate was highly effective, very well tolerated, and it reached therapeutic plasma levels without accumulation. It appears that fenofibrate can usefully be employed at this dosage in hyperlipidaemia, especially since patient compliance is better when only one daily dose need be taken.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01061412
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  • 204
    Electronic Resource
    Electronic Resource
    The effect of food on the absorption of slow-release isosorbide-5-mononitrate tablets (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 47-50 
    Details
    ISSN: 1432-1041
    Keywords: isosorbide-5-mononitrate ; food intake ; slow-release formulation ; absorption rate ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of food on the absorption characteristics of slow release isosorbide-5-mononitrate tablets was investigated in 10 normal healthy volunteers. There were no differences in the peak concentration achieved or the area under the curve, but the peak concentration occurred later when the drug was administered after food. The apparent elimination half-life ranged from 4.7 to 10.1 h. Bioavailability of slow-release isosorbide-5-mononitrate is therefore unaffected by food, but there is a slower rate of absorption.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01061416
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  • 205
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and bioavailability of intravenous and oral chlordesmethyldiazepam in humans (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 109-112 
    Details
    ISSN: 1432-1041
    Keywords: chlordesmethyldiazepam ; lorazepam ; pharmacokinetics ; i.v./p.o. administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Six healthy, fasting volunteers were given single doses of chlordesmethyldiazepam by 1 mg i. v., or as drops or tablets. Chlordesmethyldiazepam and its metabolite, lorazepam, in multiple plasma samples and in urine collected for 120 h after each dose were determined by electron-capture GLC. Mean kinetic variables for intravenous chlordesmethyldiazepam were: volume of distribution, 1.71 l · kg−1; elimination half-life, 113 h; total clearance, 0.21 ml · min−1 · kg−1; cumulative excretion of lorazepam glucuronide 24.2% of the dose. Following a lag time of 15.5 min (tablets) and 4.2 min (drops), which were significantly different, the absorption of oral chlordesmethyldiazepam was a first order process, with apparent absorption half-life values averaging 1.5 h (tablets) and 1.1 h (drops). Bioavailability was 77% for tablets and 79% for drops.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01061430
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  • 206
    Electronic Resource
    Electronic Resource
    Interaction between furosemide and the converting enzyme inhibitor benazepril in healthy volunteers (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 465-468 
    Details
    ISSN: 1432-1041
    Keywords: benazepril ; furosemide ; converting enzyme inhibitor ; pharmacokinetics ; drug interaction ; blood pressure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Single oral doses of 10 mg converting enzyme inhibitor benazepril (CGS 14824A) and 40 mg furosemide were administered to 12 healthy male volunteers either separately or concomitantly. The pharmacokinetic parameters of benazepril were not influenced by coadministration of furosemide. Urinary excretion of total furosemide was significantly reduced by 10 to 20% in the presence of benazepril. This effect was considered clinically insignificant. Erect blood pressure decreased and pulse rate increased only during concomitant treatment.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01046703
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  • 207
    Electronic Resource
    Electronic Resource
    Cyclosporin: Pharmacokinetics and detailed studies of plasma and erythrocyte binding during intravenous and oral administration (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 451-460 
    Details
    ISSN: 1432-1041
    Keywords: cyclosporin ; pharmacokinetics ; infusions ; binding ; lipids ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary On the basis that unbound concentration better correlates with response than total plasma or blood concentration, the inter- and intra-subject variability in the distribution of cyclosporin within blood and to plasma components was studied in renal transplant patients. Pharmacokinetic aspects were also studied. Blood samples were analysed from patients who received the drug both by a 72-h i.v. infusion and orally (7 mg·kg−1 twice daily). Steady-state was reached within 18 h of starting the i.v. infusion; the plasma data were best fitted by a biexponential equation with half-times of 0.13–1.02 h and 4.3–13.9 h, associated with the two phases. The mean plasma clearance was 700 ml/min. Concentrations during the infusions measured by RIA and HPLC were comparable. Oral profiles showed rapid and extensive absorption. The peak plasma concentrations were 1460–1880 µg·l−1 and occurred 2–4 h after dosing, with bioavailability estimates of 41–113%. Concentrations measured by RIA were higher than by HPLC. Blood-to-plasma concentration ratio measurements of cyclosporin at 37°C decreased with increasing plasma concentration and increased with haematocrit. Fraction unbound, measured by ultracentrifugation, was in the range 0.042–0.122 with an average of 0.068, and varied little in some patients but showed systematic changes with time in others. Cyclosporin binding was found to be related not only to the triglyceride but, more particularly, to the cholesterol-related lipoproteins in plasma. Monitoring cholesterol may be helpful in identifying patients with extremes in binding or with widely varying binding.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01046701
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  • 208
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of fluoride absorbed from dried seafoods by healthy adults (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 489-493 
    Details
    ISSN: 1432-1041
    Keywords: fluoride ; pharmacokinetics ; seafoods ; availability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Dried seafoods are a rich source of fluoride (F). The systemic availability of F from seafoods was studied in 3 healthy adults. The plasma concentration and urinary excretion of F for 24 h following the ingestion of 3.87±0.32 mg F (mean ± SD) in seafoods were compared with plasma and urine data following oral administration of 3 mg F in aqueous solution. There was a marked reduction and delay in the absorption of F from seafoods. The relative bioavailability of F from seafoods was 40.8±5.1%. These findings should be taken into consideration when determining the optimum level of daily F intake.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01046707
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  • 209
    Electronic Resource
    Electronic Resource
    The effect of pneumococcal vaccine on the disposition of theophylline (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 505-507 
    Details
    ISSN: 1432-1041
    Keywords: theophylline ; Streptococcus pneumoniae ; Bordetella pertussis ; pneumococcal vaccine ; pharmacokinetics ; chronic obstructive airway disease (COAD)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Pneumococcal vaccine is frequently given to chronic obstructive airway disease patients who are maintained on theophylline therapy. Several studies demonstrating the effect of viral and bacterial vaccines on drug metabolism prompted our evaluation of the effect of pneumococcal vaccine on theophylline pharmacokinetics. Six healthy volunteers, acting as their own controls, received 250 mg of theophylline every 8h for 12 days. Plasma area under the concentration-time curves (AUC) were measured on Days 4, 6, and 12. On Day 5 pneumococcal vaccine (0.5 ml) was given intramuscularly. No significant difference in elimination rate constant, AUC, or apparent oral clearance of theophylline was found at one or seven days after vaccine administration. These results indicate that intramuscular pneumococcal vaccine does not alter the pharmacokinetics of theophylline during chronic oral administration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01046710
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  • 210
    Electronic Resource
    Electronic Resource
    The in vitro stability of doxifluridine in whole blood and plasma (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 533-534 
    Details
    ISSN: 1432-1041
    Keywords: doxifluridine ; colorectal carcinoma ; 5′-deoxy-5-fluorouridine ; pharmacokinetics ; blood stability ; blood clearance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01046718
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  • 211
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of pefloxacin and amikacin administered simultaneously to intensive care patients (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 637-643 
    Details
    ISSN: 1432-1041
    Keywords: pefloxacin ; amikacin ; pharmacokinetics ; drug interaction ; severe infections
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Ten adult patients with severe infections in an intensive care unit were treated simultaneously with 6 mg/kg pefloxacin and 7.5 mg/kg amikacin, infused i.v. over 1 h every 12 h for 5 days. Twelve h after the last infusion, pefloxacin alone was administered orally (400 mg tablet) every 12 h for 10 days. The pharmacokinetics of pefloxacin and its main metabolites, norfloxacin and pefloxacin N-oxide, were determined after the first (Day 1) and last (Day 5) infusions and after the last oral dose (Day 15). The kinetics of amikacin was determined after the first and the last infusion. The maximal and minimal steady-state plasma concentrations of amikacin were 27.3 and 3.3 mg/l. The total plasma clearance was 83.1 and 67.0 ml/min after the first and the last infusions, respectively, and the half-life was 3.9 and 5.0 h. The maximal and minimal steady-state plasma concentrations of pefloxacin were 13.1 and 7.9 mg/l after i.v. infusion and 13.4 and 9.0 mg/l after oral administration. Pefloxacin elimination (t1/2) increased from 11.3 h after the first infusion to 19.4 h after the last infusion and 21.1 h after the last oral dose. Total body clearance decreased from 90.8 (Day 1) to 51.9 (Day 5) and 56.4 ml/min (Day 15). The volume of distribution did not change significantly over the course of pefloxacin. Mean steady-state plasma concentrations of norfloxacin and pefloxacin N-oxide were respectively 0.5–0.6 mg/l and 0.9–1.3 mg/l after intravenous and oral administration of pefloxacin. There were no pharmacokinetic interaction between the drugs. The dosage regimen led to plasma concentrations of pefloxacin and amikacin within their therapeutic range.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00615230
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  • 212
    Electronic Resource
    Electronic Resource
    The pharmacokinetics of melphalan during intermittent therapy of multiple myeloma (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 187-193 
    Details
    ISSN: 1432-1041
    Keywords: melphalan ; myelomas ; pharmacokinetics ; intermittent therapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary During intermittent melphalan-prednisone therapy the area under the plasma concentration-time curve of melphalan increased by an average of 45% after oral or intravenous administration of the drug in myeloma patients during the initial three courses at six-week intervals. The rise in melphalan plasma concentrations could not be referred to an alteration in melphalan elimination, metabolism, erythrocyte/plasma partition ratio, or protein binding. A possible explanation could be that covalent binding sites of melphalan were successively saturated during intermittent treatment, resulting in higher drug concentrations during successive courses of therapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609251
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  • 213
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and haematological effects of desmopressin (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 281-285 
    Details
    ISSN: 1432-1041
    Keywords: DDAVP ; desmopressin ; pharmacokinetics ; coagulation system ; fibrinolytic system ; granulocytes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and haematological effects of 1-deamino-8-D-arginine vasopressin (desmopressin, DDAVP) after intravenous, subcutaneous and intranasal administration has been studied in man. Using a sensitive, specific radioimmunoassay for DDAVP, the AUC was determined for each route of administration. It was not significantly different for the i.v. and s.c. routes. There was no effect of the route on the plasma half-life of DDAVP which ranged from 2.7 to 4.6 h. Absorption of DDAVP after intranasal (i.n.) administration was poor. Based on AUC data, bioavailability via the two s.c. methods and the i.n. route was 112%, 94% and 2%, respectively. DDAVP has a pronounced effect on coagulation and fibrinolytic parameters, causing a 4.0-(i.v.), 2.9- (s.c.), 3.1- (s.c.; 40 µg/ml) and 1.2- (i.n.) fold increase in factor VIII: Ag. The corresponding effect on tissue-type plasminogen activator (t-PA) was 1.9- (i.v.), 1.3- (s.c.), 2.2- (s.c.; 40 µg/ml) and 1.0- (i.n.) increase over the basal value. There was also a 1.4- to 1.6-fold increase in leukocyte count 4 h after s.c. and i.v. DDAVP. At plasma DDAVP levels greater than 300 pg/ml no correlation was found between the AUC and the maximum plasma DDAVP and biological response, which indicates a ceiling limit for exogenous stimulation of the coagulation and fibrinolytic systems.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00558266
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  • 214
    Electronic Resource
    Electronic Resource
    Liquid Chromatographic Assay and Pharmacokinetics of Quazepam and Its Metabolites Following Sublingual Administration of Quazepam (1988)
    Springer
    Pharmaceutical research 5 (1988), S. 365-368 
    Details
    ISSN: 1573-904X
    Keywords: quazepam ; metabolites ; reversed phase ; high-performance liquid chromatography ; solid-phase extraction ; plasma ; sublingual ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A reverse-phase liquid chromatographic method is described for simultaneous quantification of quazepam, and two of its metabolites, 2-oxoquazepam and N-desalkyl-2-oxoquazepam. The method uses a solid-phase extraction procedure to prepare plasma samples. After extraction, the methanolic extract is evaporated; the residue is then reconstituted in a small volume of mobile phase and chromatographed. The total chromatography time for a single sample is about 20 min. A sensitivity of 1 ng/ml for quazepam and its metabolites is attained when 1 ml of plasma is extracted. Analytical recovery of quazepam and its metabolites added to plasma ranged from 87 to 96%. The maximum within-day and day-to-day coefficients of variation for each compound at concentrations of 20 and 60 ng/ml were 7.6 and 11.2%, respectively. The method was applied to sublingual pharmacokinetic studies of quazepam in healthy volunteers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015907611170
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  • 215
    Electronic Resource
    Electronic Resource
    Comparative Pharmacokinetics of Methylprednisolone Phosphate and Hemisuccinate in High Doses (1988)
    Springer
    Pharmaceutical research 5 (1988), S. 509-513 
    Details
    ISSN: 1573-904X
    Keywords: methylprednisolone phosphate ; methylprednisolone hemisuccinate ; pharmacokinetics ; saliva analysis ; endogenous hydrocortisone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of methylprednisolone and two methylprednisolone esters, the phosphate and the hemisuccinate, were investigated after intravenous administration of the esters to 12 healthy male subjects in two different doses (250 and 1000 mg). Methylprednisolone was formed more rapidly from phosphate than from hemisuccinate. During the first 30 min methylprednisolone levels were three to four times higher after phosphate administration than after hemisuccinate. The mean residence time of the hemisuccinate was significantly longer and the total-body clearance lower than those of the phosphate. Whereas very little of the phosphate (mean, 1.7%) was eliminated unchanged into the urine, there were significant amounts of hemisuccinate (mean, 14.7%) excreted renally and therefore not bioavailable. Methylprednisolone saliva levels paralleled plasma levels; the average saliva/plasma ratio was 0.22. Neither phosphate nor hemisuccinate could be detected in saliva. An average of 7.2% of the administered dose was eliminated in the form of methylprednisolone in urine. Renal clearance was 24 ml/min and not dose or prodrug dependent. For both doses endogenous hydrocortisone levels were lowered after 24 hr. For the 1000-mg dose the depression was still significant after 48 hr. The results indicate that methylprednisolone phosphate results in a faster and more efficient conversion to its active form, methylprednisolone, than methylprednisolone hemisuccinate.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015921408870
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  • 216
    Electronic Resource
    Electronic Resource
    Cimetidine Elimination from the Cerebrospinal Fluid of the Rat (1988)
    Springer
    Pharmaceutical research 5 (1988), S. 628-633 
    Details
    ISSN: 1573-904X
    Keywords: cimetidine ; cerebrospinal fluid ; clearance ; choroid plexus ; pharmacokinetics ; transport
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The major goal of this study was to develop a small animal model that could be used to assess quantitatively the clearance of cimetidine from the cerebrospinal fluid (CSF) under relatively physiologic conditions. In addition, we addressed questions related to the pathways involved in the elimination of cimetidine from the CSF. We administered high and low bolus doses of cimetidine together with inulin, as a marker of bulk flow, into the lateral ventricle of anesthetized rats and sampled CSF from the cisterna magna. Principles of linear pharmacokinetic systems were applied to the data to obtain clearances from the CSF. The clearance of inulin was 2.02 ± 0.22 µl/min, which is in excellent agreement with the CSF production rate of 2.2 µl/min in anesthetized rats. The clearance of cimetidine from the CSF following the administration of a low dose was 11.8 ± 3.1 µl/min, which is in good agreement with the cimetidine CSF clearance in the rat obtained previously in studies using the technique of ventriculocisternal perfusion. A 32% decrease in the CSF clearance of cimetidine (P 〈 0.05) was observed when the high dose was administered, suggesting that CSF elimination is saturable. The clearance of inulin was unaffected by the high dose of cimetidine. This study demonstrates that the technique of lateral ventricle injection and sampling from the cisterna magna is useful in quantitatively assessing the elimination of compounds from the CSF in the rat under relatively physiologic conditions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015918802935
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  • 217
    Electronic Resource
    Electronic Resource
    Liquid Chromatographic Analysis of Di(2-ethylhexyl) Phthalate: Application to Pharmacokinetic Studies in the Mongrel Dog (1988)
    Springer
    Pharmaceutical research 5 (1988), S. 10-15 
    Details
    ISSN: 1573-904X
    Keywords: di(2-ethylhexyl) phthalate ; liquid chromatographic (LC) analysis ; pharmacokinetics ; renal failure ; mongrel dog
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A high-performance liquid chromatographic (HPLC) assay was developed for the determination of di(2-ethylhexyl) phthalate (DEHP) in serum or plasma. Plasma DEHP concentrations that were measured by HPLC in specimens obtained from hemodialysis patients were in good agreement with corresponding concentrations that were measured by gas chromatography with selected ion monitoring (GC-SIM) (r 2 = 0.996). Plasma DEHP concentrations were measured after intravenous DEHP administration (1.2–4.4 mg DEHP/kg body weight) to determine the effect of bilateral ureteral ligation on DEHP elimination in the mongrel dog. DEHP plasma clearance (∼6.3 ml/min/kg), steady-state distribution volume (∼0.2l/kg), and terminal half-life (∼50 min) were unchanged in two dogs following bilateral ureteral ligation. DEHP terminal half-life and steady-state distribution volume were substantially smaller (25- to 70-fold) than reported previously in the rat or dog.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015872309411
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  • 218
    Electronic Resource
    Electronic Resource
    Mean Residence Time Concepts for Pharmacokinetic Systems with Nonlinear Drug Elimination Described by the Michaelis–Menten Equation (1988)
    Springer
    Pharmaceutical research 5 (1988), S. 156-164 
    Details
    ISSN: 1573-904X
    Keywords: mean residence time ; moment analysis ; pharmacokinetics ; Michaelis–Menten elimination ; compartmental models
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Equations for the mean residence time (MRT) of drug in the body and related functions are derived for drugs which are intravenously administered into a one- or two-compartment system with Michaelis–Menten elimination. This MRT is a function of the steady-state volume of distribution and time-average clearance obtained from the dose and area under the curve (dose/AUC). The differences between the MRT calculated by the proposed method and by using the moment theory method (AUMC/AUC) are demonstrated both mathematically and by computer simulations. The validity of the proposed method for calculation of MRT and its relationship to the moment theory result have also been assessed by examining the percentage of the administered dose eliminated and the percentage of the total area attained at MRT and at AUMC/AUC in relation to the dose. The equations evolved should be helpful in clarifying residence time derivations and in defining the disposition characteristics and differences between linear and nonlinear systems. Direct methods are provided for calculation of Michaelis–Menten parameters based on the relationship between MRT and dose.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015960806202
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  • 219
    Electronic Resource
    Electronic Resource
    Capillary Gas Chromatography and Thermionic N-P-Specific Detection of 13-Bis(2-chloroethyl)-l-nitrosourea (BCNU) or l-(2-Chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU) in Stability and Pharmacokinetic Studies (1988)
    Springer
    Pharmaceutical research 5 (1988), S. 220-225 
    Details
    ISSN: 1573-904X
    Keywords: capillary gas chromatography ; analysis ; stability ; pharmacokinetics ; carmustine ; lomustine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract An expedient, rapid, and sensitive capillary gas chromatographic method for the analysis of l,3-bis(2-chloroethyl)-l-nitrosourea (BCNU) or l-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU) in plasma is described. Separation of the underivatized nitrosourea compounds was performed on a 0.33-mm-i.d., 25-m fused-silica, SE-30 capillary column, and detection was carried out using a thermionic N–P-specific detector. The compounds were extracted from plasma with benzene with a yield of 〉87%. The assay was linear in the ranges of 0.001 to 0.5 and 0.5 to 25 µg/ml for CCNU or 0.003 to 0.50 and 0.5 to 25 µg/ml for BCNU, with correlation coefficients from 0.9914 to 0.9999 and coefficients of variation (CV) of 〈3.3%. Other antineoplastic agents did not interfere in the assay. The method was employed to study the pharmacokinetics of BCNU in rabbits. The plasma concentration-time curves were fit to a two-compartment model with a mean (SE) α, β, and total-body clearance of 2.898 (0.913) hr−1, 0.1228 (0.0179) hr−1, and 7.211 (2.862) liters/hr · kg, respectively. Further, the stability of BCNU and CCNU in solution was examined at different temperatures. Both compounds were stable in benzene or acetone (4 to 37°C) but labile in plasma even if refrigerated. The apparent rate constants for degradation of BCNU and CCNU were 0.09921 and 0.02853 hr−1 at 4°C and 5.998 and 2.553 hr−1 at 37°C, respectively.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015989612562
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    Dextromethorphan Pretreatment Induces Antipyrine Clearance in the Rat (1988)
    Springer
    Pharmaceutical research 5 (1988), S. 437-439 
    Details
    ISSN: 1573-904X
    Keywords: antipyrine ; dextromethorphan ; drug metabolism ; enzyme induction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Numerous agents that undergo extensive first-pass metabolism have been shown to inhibit oxidative drug metabolism. To examine whether this effect is related to the chemical structure or pharmacokinetic characteristics of the inhibiting agent, we determined the effect of dextromethorphan (a compound which exhibits pharmacokinetic similarities to, but is chemically dissimilar from, previously studied agents) on the disposition of antipyrine. A single oral dose of dextromethorphan hydrobromide, 100 mg/kg, 1 hr prior to antipyrine administration had no significant effect on the pharmacokinetics of this model substrate. The administration of dextromethorphan at the same dose twice daily for 3 days and an additional dose 1 hr prior to antipyrine administration resulted in a 33% increase in the clearance of antipyrine. These data indicate that dextromethorphan is capable of inducing hepatic microsomal enzymes. Studies are needed to determine if this effect also occurs upon chronic administration in humans. These data suggest that the pharmacokinetic characteristic of extensive first-pass metabolism is not necessarily associated with inhibition of drug metabolism.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015940518439
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    Quantitative Structure–Activity Study on Human Pharmacokinetic Parameters of Benzodiazepines Using the Graph Theoretical Approach (1988)
    Springer
    Pharmaceutical research 5 (1988), S. 201-208 
    Details
    ISSN: 1573-904X
    Keywords: quantitative structure–activity analysis (QSAR) ; topological approach ; benzodiazepines ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The graph theoretical indices for a series of 13 benzodiazepines were calculated using a graph-path topological method. The total molecule, the ring fragments, and combinations of ring fragments were subjected to a quantitative structure–activity analysis using eight pharmacokinetic parameters. The metabolic clearance and the blood-to-plasma concentration ratios were most highly correlated with the graph theoretical indices, with R values of 0.975 and 0.938, respectively. These correlations were found when the diazepine + benzo fragment and phenyl fragment were used to calculate the graph-path indices. Terminal disposition half-life was correlated with the benzo + diazepine fragment, with R = 0.969. Truncating the graph-path codes by eliminating cycles in the total molecule markedly improved the correlation coefficients. When compared to the graph-path indices for the total molecule, the correlation coefficients for the terminal disposition half-life and metabolic clearance data rose from 0.721 to 0.935 and from 0.770 to 0.968, respectively, using the graph-path indices of the truncated molecule. Intrinsic clearance of unbound drug also was poorly correlated with the total molecule (r 〈 0.7) but rose significantly using the graph-path indices of the truncated moleucle (r = 0.971 and 0.975 for the well-stirred and parallel-tube models, respectively.)
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015933527583
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    Pharmacokinetics, behavioral, and neurophysiological aspects of the action of 2-ethyl-6-methyl-3-hydroxypyridine in rats (1988)
    Springer
    Bulletin of experimental biology and medicine 106 (1988), S. 1104-1107 
    Details
    ISSN: 1573-8221
    Keywords: nootropic drugs ; pharmacokinetics ; behavior ; rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00840370
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    An Implantable Pump for Intrarenal Infusion of Immunosuppressants in a Canine Autotransplant Model (1988)
    Springer
    Pharmaceutical research 5 (1988), S. 781-785 
    Details
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; 6-mercaptopurine ; targeted drug delivery ; renal transplantation ; intraarterial infusion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract We developed a canine renal allograft model utilizing implantable infusion pumps and biocompatible catheters to investigate the pharmacokinetics of local immunosuppressive drug administration. Seven mongrel dogs underwent bilateral nephrectomy and autotransplantation of one kidney to the iliac vessels. The proximal end of an infusion catheter directed into the iliac artery was tunneled to a subcutaneously placed programmable pump. A second, sampling catheter was placed with its tip in the iliac vein. Simultaneous regional (iliac vein) and systemic (jugular vein) venous concentrations of 6-mercaptopurine (6-MP), the immunosuppressive metabolite of azathioprine, were determined during a continuous 24-h intraarterial infusion (10 mg/kg/24 hr). The gradient between regional and systemic 6-MP concentrations was maximal initially when the pump was turned on, continuously decreased until steady state was reached, and disappeared immediately after the pump was turned off. The mean ratio of steady-state iliac vein to systemic 6-MP concentrations was 5.0 ± 1.4, demonstrating a pharmacokinetic advantage of continuous intraarterial 6-MP infusion to the autotransplanted kidney. The novel canine renal allograft model described herein overcomes the technical limitations of earlier models and represents a foundational step in the design of intrarenal infusion patterns of immunosuppressive agents which we expect to prolong survival of the allotransplanted kidney with minimal systemic drug exposure and side effects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015940802451
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  • 224
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    Pharmacokinetics and Bioavailability of Hydromorphone: Effect of Various Routes of Administration (1988)
    Springer
    Pharmaceutical research 5 (1988), S. 718-721 
    Details
    ISSN: 1573-904X
    Keywords: hydromorphone ; intranasal ; transdermal ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics and bioavailability of hydromorphone following various routes of administration, i.e., intravenous, oral, intranasal, and transdermal, were investigated in rabbits. Hydromorphone plasma concentrations were determined by reverse-phase high-performance liquid chromatography (HLPC). Comparison of area under the concentration versus time curve (AUC) between intravenous and oral administrations showed a low bioavailability of hydromorphone after oral administration. The nasal absorption of hydromorphone was studied by the in situ nasal recirculation technique, and the results showed that hydromorphone is well absorbed from the nasal mucosa. The transdermal permeation of hydromorphone was also evaluated for 24 hr and a steady-state plasma concentration (0.135 µg/ml) was achieved during the 6- to 24-hr periods following the application of a transdermal patch on the inner pinna of the rabbit's ear.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015959912021
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  • 225
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    Exogenous Methemoglobin as a Cyanide Antidote in Rats (1988)
    Springer
    Pharmaceutical research 5 (1988), S. 749-752 
    Details
    ISSN: 1573-904X
    Keywords: methemoglobin ; cyanide antidote ; cyanide poisoning ; pharmacokinetics ; rats
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The effects of the administration of methemoglobin (MetHb) prepared in vitro were evaluated in Sprague–Dawley rats given increasing doses of potassium cyanide (KCN). Median lethal dose (LD50) studies were conducted by giving intraperitoneal injections of KCN (in 0.3- to 0.5-ml volumes), then 2 min later administering intravenous (iv) doses of 1000, 1500, or 2500 mg/kg of MetHb through the tail vein. Control rats received an equivalent volume of saline. The resulting LD50 values for KCN were 7.4 ± 1.1, 11.7 ± 1.1, 13.9 ± 1.0, and 14.2 ± 1.0 mg/kg (mean ± SD) for the control (no MetHb) and 1000-, 1500-, and 2500-mg/kg dose groups, respectively. Additional groups of rats were given 1000, 1500, or 2500 mg/kg MetHb and submitted for necropsy. The gross finding of darkened kidneys was present in both dose groups, but became consistent and more prominent in the 2500-mg/kg dose group. Evidence of pathologic changes was not present in other organs. Single-dose pharmacokinetic studies were conducted using iv doses of 1600 and 2500 mg/kg MetHb. The elimination half-life was similar in both doses (62.6 min), but the volume of distribution (95.3 ± 7.2 and 126.3 ± 5.2 ml/kg, mean ± SE) and clearance (1.1 ± 0.1 and 1.5 ± 0.1 ml/min/kg) were significantly different (P 〈 0.05) for the 1600-and 2500-mg/kg dose groups, respectively. From these data we conclude that although MetHb is cleared from the vascular system rapidly, it may be an effective and nontoxic antidote for doses of cyanide up to twice that of the control LD50.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015928432494
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    Calculations and Application of Mean Residence Times for Drugs Which Demonstrate One-Compartment Distribution and Michaelis-Menten Elimination (1988)
    Springer
    Pharmaceutical research 5 (1988), S. 196-196 
    Details
    ISSN: 1573-904X
    Keywords: mean residence time ; pharmacokinetics ; Michaelis-Menten elimination ; one-compartment model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015977209836
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    Stereoselective Binding of Disopyramide to Plasma Proteins (1988)
    Springer
    Pharmaceutical research 5 (1988), S. 316-318 
    Details
    ISSN: 1573-904X
    Keywords: disopyramide ; pharmacokinetics ; plasma proteins ; stereoisomers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015986906627
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    Preliminary evaluation of potential anti-epileptic drugs by single dose electrophysiological and pharmacological studies in patients (1988)
    Springer
    Journal of neural transmission 72 (1988), S. 259-266 
    Details
    ISSN: 1435-1463
    Keywords: Anti-epileptic drugs ; pharmacokinetics ; EEG ; photosensitivity ; drug interactions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In phase 1 evaluation of potential anti-epileptic drugs (AEDs), insufficient attention has perhaps been directed to the transition from single, and multi-dose studies in normal volunteers to clinical trials of some weeks duration in patients. Acute single dose studies in epileptic patients already receiving AEDs may reduce avoidable errors in early controlled trials. Acute single dose studies provide the opportunity of obtaining some preliminary evidence of efficacy by observing the effects of the drug on quantified epileptiform EEG discharges, both those occurring spontaneously in long term telemetric recordings and those elicited by standardised photic stimulation in susceptible subjects. The pharmacokinetics of the new drug may be profoundly influenced by the comedication (as illustrated by lamotrigine, the half life of which varies by a factor of 10 depending on comedication). Conversely, the new drug may so influence metabolism of the comedication that the results of add-on trials may be virtually uninterpretable, unless steps are taken to maintain blood levels of the other AEDs. A method of addressing this problem is illustrated in the case of an imidazole, R 57720. Adverse experiences may also occur more readily when a new drug is added to comedication than when it is given to normal volunteers and these problems in chronic trials can be anticipated from acute studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01243424
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    Intrathecal ACNU — a new therapeutic approach against malignant leptomeningeal tumors (1988)
    Springer
    Journal of neuro-oncology 6 (1988), S. 221-226 
    Details
    ISSN: 1573-7373
    Keywords: leptomeningeal tumor ; intrathecal chemotherapy ; ACNU ; nitrosourea ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Pharmacokinetics, toxicity and therapeutic efficacy of intrathecal ACNU, 3-((4-amino-2-methyl-5-pyrimidinyl)methyl)-1-(2-chloroethyl)-1-nitrosourea, were studied in rats to determine if it is a new and effective method for the treatment of malignant leptomeningeal tumors. Pharmacokinetics of intracisternally administered ACNU was studied by macroscopial autoradiography using 14C-labeled ACNU. It was demonstrated that intracisternally administered ACNU distributed in the subarachnoid space and subpial layer of the brain in high concentration and was rapidly eliminated into the systemic circulation. The diffusional transport of ACNU into the deeper part of the brain was limited. More than 3.0 mg/kg of intracisternal ACNU induced progressive loss of the weight of body in normal rats, and 80% of the rat given 6.0 mg/kg died. Increase of capillary permeability, neuronal loss and gliosis were observed in the marginal layer of the brain facing to the subarachnoid space in the rat given more than 3.0 mg/kg of ACNU. Systemic and local toxicity was not observed in the rat given less than 1.5 mg/kg. Therapeutic effect of intrathecal ACNU against leptomeningeal tumors was evaluated in the rat with meningeal carcinomatosis induced by intracisternal inoculation of Walker 256 carcinosarcoma cells. The median survival time of the rat treated with 1.5 mg/kg of intracisternal ACNU once on day 2 or on day 5 after tumor inoculation was significantly prolonged by 173%, and 214% at maximum, respectively, as compared with that of the untreated animal. These findings suggest that intrathecal ACNU may be of value for clinical trial against leptomeningeal tumors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00163704
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    Peripheral pharmacokinetic parameters of levodopa/carbidopa and the on-off phenomenon in parkinsonian patients (1988)
    Springer
    Neurological sciences 9 (1988), S. 255-259 
    Details
    ISSN: 1590-3478
    Keywords: Parkinson disease ; levodopa ; pharmacokinetics ; on-off phenomenon
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Sommario I principali parametri farmacocinetici periferici della associazione levodopa/carbidopa sono stati studiati in 11 volontari sani ed in 16 pazienti affetti da morbo di Parkinson in differenti stadi di malattia, con e senza fluttuazioni delle performances motorie. Dopo somministrazione per via orale di una dose standard del farmaco (levodopa 250 mg., carbidopa 25 mg.), i valori della concentrazione plasmatica massima, del tempo di comparsa del picco e dell'area sotto la curva concentrazione/tempo sono risultati simili in tutti i gruppi esaminati. La farmacocinetica periferica dell'associazione levodopa/carbidopa non è risultata essere differente nei parkinsoniani che presentavano delle fluttuazioni delle performances motorie in confronto ai pazienti con stabile risposta clinica alla terapia.
    Notes: Abstract The principal peripheral pharmacokinetic parameters of the levodopa/carbidopa association were investigated in 11 healthy volunteers and in 16 patients at various stages of Parkinson disease, with and without the on-off phenomenon. After oral administration of a standard dose of drug (levodopa 250 mg + carbidopa 25 mg) the peak plasma concentrations, peak onset time and area under the curve/time proved to be similar across the groups. There was no difference in peripheral pharmacokinetics of the association between parkinsonian patients with swings in response and those without.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02334049
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    On the dose dependency of Cyclosporin a absorption and disposition in healthy volunteers (1988)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 16 (1988), S. 331-353 
    Details
    ISSN: 1573-8744
    Keywords: Cyclosporin A ; pharmacokinetics ; dose dependency ; oral absorption ; disposition ; healthy subjects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of Cyclosporin A (CyA, SandimmuneR) was studied in 12 healthy male volunteers after oral dosing of 350 mg, 700 mg, and 1400 mg as a drinking solution. Blood samples were collected over 96 hr and analyzed by high pressure liquid chromatography. Concentration data were evaluated with model-independent and model-based linear pharmacokinetic concepts. Individual CyA concentration-time profiles in whole blood were well described by a two-compartment open model with zero-order absorption for all three doses. Comparison of pharmacokinetic parameters across doses indicates that both absorption and disposition are dose-dependent. Nonlinear disposition is suggested by the significant increase of the terminal half-life from 8.9±4.9hr to 11.9±4.9hr (mean±SD) after a 350 mg and a 1400 mg dose, respectively. Changes in the metabolic activity of the liver with concentration might be responsible for this phenomenon. In addition, the modeling approach indicated that bioavailability decreases with increasing dose. Moreover, the dependence of the rate of CyA absorption (zero-order rate constant) versus dose was well described by a hyperbola. The limited solubility of the drug in the gastrointestinal tract might be responsible for this behavior. The lag time (0.2–0.8 hr) was independent of dose. This value is similar to the time of gastric emptying in fasting volunteers. The duration of absorption for 11 of 12 subjects was in the range 2.5–3.5 hr over all doses and agrees well with the small intestine transit time. Some subjects showed a marked secondary peak at one or two doses, which could be adequately fitted by a model with two successive zero-order inputs. This double-peak behavior was ascribed to the influence of the food on gastric emptying. Dose dependency of disposition and absorption counterbalance each other in the usual dose range. This leads to an almost proportional increase of area under the blood CyA concentration-time profile with increasing dose.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01062550
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    The use of mass balance principles to describe regional drug distribution and elimination (1988)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 16 (1988), S. 13-29 
    Details
    ISSN: 1573-8744
    Keywords: pharmacokinetics ; mass balance ; regional distribution ; regional elimination
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Mass balance principles were used to derive a number of terms that are helpful in describing the rate and extent of regional drug uptake. Regional drug uptake was defined as the net movement of drug from the blood perfusing a region into the extravascular space of the region due to the distribution and/or elimination of the drug. By analogy with the traditional physiological definition of flux, net drug flux was defined as the difference in mass per unit time of drug respectively entering and leaving a region via the arterial and venous blood vessels. The timeintegral of net drug flux, net drug mass, was defined as the mass of drug that has entered a region via the arterial blood vessels but has not left the region via the venous blood vessels. For regions in which no drug elimination occurs, the mean regional drug concentration was defined as the net drug mass divided by the mass of the region. When a number of criteria are satisfied, the net drug flux is approximately the rate of drug uptake and the net drug mass is approximately the extent of drug uptake. Several examples are given to demonstrate the broad range of applications of mass balance principles. First, the method was used to characterize the differences between drug distribution and elimination in a hypothetical region using drug concentrations simulated from compartmental models of either distribution alone or distribution with elimination. Second, the whole body distribution net flux was described during a constant rate infusion of iodohippurate (IOH) into a sheep from the difference between the whole body net flux and renal net flux of IOH. Third, the time course of the mean myocardial lignocaine (lidocaine) concentrations in a sheep after an intravenous bolus of lignocaine were described. The time course of the lignocaine-induced depression of myocardial contractility followed more closely the mean myocardial lignocaine concentrations than that of either the arterial or coronary sinus blood concentrations. It is concluded that the use of mass balance principles provides a simple, empirical, and physiologically based method for the determination of the rate and extent of both drug distribution and elimination in regions as simple as single organs or as complex as the whole body.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01061860
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    The uptake and elution of lignocaine and procainamide in the hindquarters of the sheep described using mass balance principles (1988)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 16 (1988), S. 31-40 
    Details
    ISSN: 1573-8744
    Keywords: lignocaine ; procainamide ; pharmacokinetics ; mass balance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Mass balance principles were used to describe the uptake and elution of lignocaine (lidocaine) and procainamide in the hindquarters of the sheep. Each of four sheep received a right atrial infusion of either lignocaine · HCl (2.7 mg/min) or procainamide · HCl (5.5mg/min) for 180 min. Paired arterial and inferior vena cava (draining the hindquarters) blood samples were taken at 20-min intervals during the infusion and for 180 min after the infusion. Lignocaine and procainamide mean total body clearances were 2.9 L/min (SD 1.1) and 1.3 L/min (SD 0.2), respectively. An index of the uptake and elution of these drugs in the hindquarters was estimated from the net drug mass per unit hindquarter blood flow;indirect evidence suggested that hindquarter blood flow was constant. All the net mass/flow of procainamide that was taken into the hindquarters during the infusion also eluted after the infusion, demonstrating reversible distribution into the tissues. However, uptake of procainamide was still occurring when blood concentrations were constant, indicating that the concentrations of procainamide in the hindquarters were not in equilibrium with the inferior vena cava concentrations. Lignocaine did not reach constant blood concentrations during the infusion and showed no tendency to reach arteriovenous equilibration; an arteriovenous difference of 22%(SD5%) across the hindquarters was measured during the last 60 min of the infusion. By 180 min after the lignocaine infusions, 79% (SD 8%) of the lignocaine net mass/flow had not eluted from the hindquarters when arterial and venous lignocaine concentrations were not significantly different. This drug could remain uneluted due to metabolism and/or avid tissue binding, and presents difficulties in the interpretation of pharmacokinetic data whether based on arterial or venous blood sampling.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01061861
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    Pharmacokinetic modeling of the anticonvulsant response of oxazepam in rats using the pentylenetetrazol threshold concentration as pharmacodynamic measure (1988)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 16 (1988), S. 203-228 
    Details
    ISSN: 1573-8744
    Keywords: oxazepam ; pharmacokinetics ; pharmacodynamics ; anticonvulsant response ; pentylenetetrazol threshold ; kinetic-dynamic model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract This investigation developed strategies along which the anticonvulsant effect of oxazepam in the rat could be pharmacokinetically modeled. After determination of the pharmacokinetics of oxazepam, which could be described with a two-compartment model (halflives of distribution and elimination 6 and 52 min, respectively), the drug was administered iv to groups of animals to achieve a serum concentration range of 0.1–2.5 mg/L at 10, 45, and 120 min after administration. At these time points pentylenetetrazol (PTZ) was infused slowly until the first myoclonic jerk occurred. The anticonvulsant response, expressed as the elevation of the serum or brain threshold concentration of PTZ, was modeled versus the serum (both total and free) and brain oxazepam concentration, according to the sigmoid E max model. The total serum and brain oxazepam EC50 values are about 0.5 mg/L and 1.1 mg/kg, respectively, and E max 120 mg/L PTZ. No marked differences in pharmacodynamic parameters between the three time groups were found, which indicates that serum and brain are pharmacokinetically indistinguishable from the effect compartment, that there is no (inter) activity of oxazepam metabolites and absence of development of acute tolerance during the investigated time frame. An interfering role of metabolites was also excluded by a direct radioreceptor assay of oxazepam, yielding very similar results as the specific Chromatographic assay. It is concluded that the concentration-anticonvulsant effect relationship of oxazepam can satisfactorily be described by the sigmoid E max model, when utilizing the employed experimental strategies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01062261
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    Kinetics of cotinine after oral and intravenous administration to man (1987)
    Springer
    European journal of clinical pharmacology 31 (1987), S. 583-588 
    Details
    ISSN: 1432-1041
    Keywords: cotinine ; pharmacokinetics ; non-smokers ; absolute bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Cotinine, the main metabolite of nicotine, was administered intravenously to healthy male non-smoking volunteers in doses of 5, 10 and 20 mg, and orally in doses of 10 and 20 mg. Intravenous administration was characterized by a dose-independent half-life of 12.2 h, mean residence time of 15.9 h, total clearance of 3.64 l h−1 and a volume of distribution of 56.5 l. Renal clearance was 0.46 l h−1 and approximately 12.0% of the dose was excreted unchanged in the urine. The mean absorption time after oral dosing ranged between 1 and 3 h, the peak concentration was reached within 45 min and the mean elimination half-lives were 12.9 and 11.7 h, respectively, after the 10 and 20 mg doses. Systemic bioavailability ranged between 0.84 and 1.11 following 10 mg and between 0.97 and 1.03 following the 20 mg dose. Mean urinary recovery and renal clearance were almost identical with the values after iv administration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00606635
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    The effects of obesity and exercise on the pharmacokinetics of caffeine in lean and obese volunteers (1987)
    Springer
    European journal of clinical pharmacology 31 (1987), S. 595-600 
    Details
    ISSN: 1432-1041
    Keywords: caffeine ; exercise ; obesity ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of obesity, exercise, and the interaction of obesity and exercise were examined in 6 caffeine naive, untrained, nonsmoking, college males (3 lean (LV), 3 obese (OV)). Each subject received caffeine (oral, 5.83 mg·kg−1 lean body weight) or placebo (50 mg citrate) prior to 3 h of seated rest and prior to 90 min of treadmill walking (40% of their maximal aerobic power) followed by 90 min of seated recovery. Serum samples were collected at various times and analyzed for caffeine by HPLC. Pharmacokinetic analysis indicated that at rest, OV had a significantly higher absorption rate constant (Ka 0.0757 vs. 0.0397 min−1), lower elimination rate constant (Ke 0.0027 vs. 0.0045 min−1), and longer serum half-life (t1/2 4.37 vs. 2.59 h) in comparison to LV. In exercise, as well as at rest LV and OV had a large difference in the volume of distribution (43.2 vs. 101. 1) (rest, 54.1 vs. 103.1). Exercise consistently resulted in a decrease in the maximal serum concentration of caffeine and the area under the curve in OV while having no consistent effect on LV. The interactive effects of obesity and exercise could not be dissociated. However, these results demonstrate that both obesity and exercise have modified the pharmacokinetics of caffeine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00606637
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    The chronopharmacokinetics of indomethacin suppositories in healthy volunteers (1987)
    Springer
    European journal of clinical pharmacology 31 (1987), S. 617-619 
    Details
    ISSN: 1432-1041
    Keywords: chronopharmacology ; indomethacin ; suppository ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of a single 100 mg indomethacin suppository were studied in 12 healthy volunteers on two occasions at least 7 days apart. Suppositories were administered in randomised order at 9.00 and 21.00 hours to see if there was evidence of a diurnal variation in kinetic parameters. The study failed to show a significant change in single dose kinetics with the time of suppository administration. This is in contrast to previous work [1] demonstrating a circadian rhythm in the kinetics of a single oral dose of indomethacin. This suggests that the chronopharmacokinetics of indomethacin is dependent on the function of the upper gastrointestinal tract.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00606642
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    Verapamil and norverapamil in plasma and breast milk during breast feeding (1987)
    Springer
    European journal of clinical pharmacology 31 (1987), S. 625-627 
    Details
    ISSN: 1432-1041
    Keywords: verapamil ; breast milk ; norverapamil ; breast feeding ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The concentrations of verapamil and norverapamil have been measured in milk and plasma samples from a 32year-old woman treated with verapamil 80 mg tds while breast-feeding her child. The average steady-state concentrations of verapamil and norverapamil in milk were, respectively, 60% and 16% of the concentrations in plasma. The breast-fed child received less than 0.01% of the dose of verapamil given to the mother. No verapamil or norverapamil (〈1 ng/ml) could be detected in the plasma from the child.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00606644
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  • 239
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    Effect of miocamycin on theophylline kinetics in children (1987)
    Springer
    European journal of clinical pharmacology 31 (1987), S. 701-704 
    Details
    ISSN: 1432-1041
    Keywords: theophylline ; miocamycin ; drug interaction ; metabolism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The interaction between a new macrolide antibiotic, miocamycin, and theophylline was evaluated in a single cross-over study in 5 asthmatic children. Each patient received a single dose of theophylline (4.3 mg/kg) delivered in 15 min using a constant-rate infusion pump, immediately before and after a 10 day course of miocamycin 17.5 mg/kg b.d. The pharmacokinetics of theophylline were calculated for each phase of the study. The elimination rate constant (3.92 vs 3.74 h−1), the mean total body clearance (1.71 vs 1.8 ml·min·kg−1) and the mean apparent volume of distribution (0.57 vs 0.58 l·kg−1) did not differ. The result can be explained by the inability of the antibiotic to form inactive cytochrome P-450 metabolite complexes which can interfere with the metabolism of theophylline. Thus, miocamycin can safely be administered to asthmatic children requiring theophylline treatment, when they have an infection due to susceptible pathogens.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00541298
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    Pharmacokinetics of meptazinol after parenteral administration in the elderly (1987)
    Springer
    European journal of clinical pharmacology 31 (1987), S. 733-736 
    Details
    ISSN: 1432-1041
    Keywords: meptazinol ; pharmacokinetics ; elderly patients ; healthy volunteers ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have determined the pharmacokinetics of meptazinol after its intravenous and intramuscular administration in a crossover study in 7 elderly hospital in-patients (〉70 years), and have compared with the results from 14 healthy, young volunteers (ages 20–40 years). The systemic availability after i.m. administration was comparable to that after i.v. administration, a result consistent with the physicochemical properties of the drug. There was a slight, but statistically significant (p〈0.01) prolongation in t1/2z in the elderly (mean 2.93 h) compared with the young (mean 2.06 h). This was associated with a 25% lower clearance in the elderly rather than with any alteration in volume of distribution. However, these changes would not appear to be substantial enough to require a revised dosage recommendation for meptazinol for this age group.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00541306
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  • 241
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    Variation in chloroquine pharmacokinetics due to assay sensitivity and duration of sampling (1987)
    Springer
    European journal of clinical pharmacology 31 (1987), S. 743-743 
    Details
    ISSN: 1432-1041
    Keywords: chloroquine ; dose dependence ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00541310
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  • 242
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    Acute renal effects of oral felodipine in normal man (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 17-22 
    Details
    ISSN: 1432-1041
    Keywords: felodipine ; calcium antagonist ; normal man ; renal function ; albumin excretion ; beta2-microglobulin excretion ; adverse effects ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The acute renal effects of a single oral dose of felodipine 0.15 mg/kg were studied in 8 healthy males. Thirty minutes after administration the mean plasma concentration was 25.7 nmol/l. There was a significant reduction in diastolic blood pressure (24%) and a concomitant rise in heart rate (38%), leaving the systolic pressure unchanged. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured by the constant infusion technique using the clearance of125I-iothalamate and131I-hippuran respectively. GFR was unchanged and the filtration fraction (FF) was reduced, whilst there was a decrease in renal vascular resistance (RVR). The glomerular filter characteristics were unchanged, as estimated by the unchanged excretion rate of albumin. There was a significant rise in the clearance of sodium (176%) but only a small and insignificant increase in urine volume. Clearance of potassium was decreased. An increase in the clearance of uric acid and a rise in the beta-2-microglobulin excretion rate were found, both suggesting a proximal tubular effect of felodipine. The excretion rate of calcium was increased.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609952
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    A comparative study of the pharmacokinetics and pharmacodynamics of atenolol, hydrochlorothiazide and amiloride in normal young and elderly subjects and elderly hypertensive patients (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 53-60 
    Details
    ISSN: 1432-1041
    Keywords: atenolol ; amiloride ; hydrochlorothiazide ; young ; elderly ; pharmacokinetics ; pharmacodynamics ; volunteers ; patients ; hypertension
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Six normal young and six normal elderly volunteers and six elderly hypertensive patients took part in an acute and chronic dose study of a combination capsule containing atenolol (50 mg), hydrochlorothiazide (25 mg) and amiloride (2.5 mg) designed for the treatment of hypertension. No difference in any of the drug pharmacokinetic parameters could be detected between the hypertensives and the normal elderly subjects. The bio-availability and the 24-h blood concentrations of all three drugs, half-life of atenolol and amiloride and the peak concentration of hydrochlorothiazide was significantly greater in the elderly. The 24-h blood concentrations of atenolol and hydrochlorothiazide did not alter with chronic dosing, but amiloride concentrations were significantly higher at this time in all groups. A significant fall in the blood pressure was observed in the hypertensive group. Heart rate fell more in the normal and hypertensive elderly subjects than in the young. The combination has shown to be an effective and well tolerated antihypertensive in the elderly patient with a 24-h duration of action.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609957
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    The pharmacokinetics of captopril and captopril disulfide conjugates in uraemic patients on maintenance dialysis: Comparison with patients with normal renal function (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 267-271 
    Details
    ISSN: 1432-1041
    Keywords: captopril ; uraemia ; captopril disulfide ; dialysis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have measured the plasma concentrations of captopril and total disulfide conjugates of captopril after a 50 mg oral dose in 6 uraemic patients on maintenance dialysis and in 8 hypertensive subjects with normal renal function. The mean peak plasma concentration of captopril was 2.5 times higher (0.447 µg·ml−1 vs 0.181 µg·ml−1) and the concentrations of the disulfides 4 times higher (3.62 µg·ml−1 vs 0.924 µg·ml−1) in the uraemic patients. Moreover captopril disulfide conjugates in the uraemic subjects reached peak concentrations at 8 h after the dose and subsequently felt. The apparent plasma half-time was 46±19 h. Only 15% of these conjugates were removed by dialysis. This marked accumulation of captopril conjugates was associated with a sustained fall in both systolic and diastolic blood pressures. In uraemic patients the mean maximum reduction in systolic and diastolic blood pressures were 37±7 mmHg and 24±9 mmHg respectively, occurring 6 h after the dose, compared with 8±7 and 8±1 mmHg respectively at 30 min in normal renal function patients. These results are consistent with the results of animal experiments, which show that captopril disulfides can be converted back to free captopril and can contribute to the antihypertensive effect of the drug. They provide a reationale for reducing the dose and frequency of administration of captopril in patients with significant renal impairment.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00607574
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  • 245
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    The effect of propranolol on exercise induced tachycardia is determined by plasma concentration and the density of adrenergic receptors on leukocytes (1987)
    Springer
    European journal of clinical pharmacology 31 (1987), S. 667-672 
    Details
    ISSN: 1432-1041
    Keywords: adrenergic beta-receptors ; propranolol ; beta-blockade ; pharmacokinetics ; leukocyte beta-receptors ; leukocytes ; exercise tachycardia ; 4—OH-propranolol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The chronotropic response to a single oral dose of propranolol in 23 healthy subjects has been related to the plasma propranolol concentration and the density of β-adrenoceptors on peripheral polymorphonuclear leucocytes. The percentage reduction in exercise-induced tachycardia was significantly correlated with the log plasma propranolol concentration within subjects but not between subjects. Taking the concentration of the active metabolite 4-hydroxypropranolol into account did not improve the interindividual correlation. The reduction in exercise-induced tachycardia was significantly correlated with the maximum binding density of (125I)-hydroxybenzylpindolol on polymorphonuclear leucocyte membrane fragments measured before medication. A response index (% reduction in exercise-induced tachycardia/plasma propranolol concentration) was correlated with the maximum binding density of (125I)-hydroxybenzylpindolol (predrug) at 2 h (rs=0.72), 4 h (rs=0.84) and 6 h (rs=0.73) after dosing. The data suggest that interindividual variation in the response to propranolol after a single oral dose is determined by interindividual differences both in plasma propranolol and adrenoceptor density.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00541293
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    Pharmacokinetics of doxorubicin in sarcoma patients (1987)
    Springer
    European journal of clinical pharmacology 31 (1987), S. 695-699 
    Details
    ISSN: 1432-1041
    Keywords: doxorubicin ; sarcoma ; pharmacokinetics ; polychemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of doxorubicin has been studied in 26 sarcoma patients receiving polychemotherapy. Mean elimination half-life was 34.7±16.6 h and the total plasma clearance was 29.5±9.31·h−1·m−2. No relationship was found between the pharmacokinetic parameters and the response to treatment, or its toxicity. Special attention was paid to the early-phase kinetics of the drug (3–20 min after injection). A correlation between the early clearance and the ages of the patients was observed. The early clearance was clearly correlated with the total plasma clearance measured over 48 h after injection, indicating the importance of the distribution phase in the overall kinetics of the drug.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00541297
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  • 247
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    Haemodilution therapy in ischaemic stroke: Plasma concentrations and plasma viscosity during long-term infusion of dextran 40 or hydroxyethyl starch 200/0.5 (1987)
    Springer
    European journal of clinical pharmacology 31 (1987), S. 705-710 
    Details
    ISSN: 1432-1041
    Keywords: dextran ; hydroxyethylstarch ; haemodilution ; ischaemic stroke ; plasma viscosity ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 21 patients with ischaemic strokes we have monitored plasma viscosity, total plasma concentration, numeric average molecular weight (Mn), and weight average molecular weight (Mw) of Dextran 40 (dextran) and hydroxyethylstarch 200/0.5 (HES) during 10 days of treatment (days 1–4, 2×500 ml; days 5–10, 1×500 ml). Plasma concentrations of dextran increased during the first 4 days (8.3 mg·ml−1 on the first day to 18.0 mg·ml−1 on the fifth day), reached an apparent steady state of 17.2 mg·ml−1 during the next 6 days, and declined subsequently with a half-time (t1/2) of 4.03 days. After ten days treatment Mn and Mw were shifted towards higher values. Plasma viscosity increased from 1.26 mPas to 1.69 mPas on Day 10 (p〈0.01) and was linearly correlated with the total plasma concentration of dextran (p〈0.001; r=0.88). Total plasma concentrations of HES averaged 11.7 mg·ml−1 on Day 1 and 12.4 mg·ml−1 on Day 5. The molecular weight distribution did not change during the infusions but decreased in comparison with the administered solution. Plasma viscosity fell from 1.40 mPas to 1.30 mPas at Day 10 (p〈0.05) and was not related to the concentration of HES. The haemodiluting effect, as indicated by a decrease of the haematocrit, was 22% and 16.8% for dextran and HES respectively. These data suggest several advantages of HES compared with dextran in haemodilution therapy of ischaemic stroke.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00541299
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    Apparent dose-dependence of chloroquine pharmacokinetics due to limited assay sensitivity and short sampling times (1987)
    Springer
    European journal of clinical pharmacology 31 (1987), S. 729-731 
    Details
    ISSN: 1432-1041
    Keywords: chloroquine ; pharmacokinetics ; dose-dependence ; exponential equations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have shown that apparent nonlinearities in the pharmacokinetics of chloroquine and wide variability in reported kinetic values are possibly artefacts of experimental design. We have used simulated data based on linear equations to demonstrate that chloroquine kinetics may appear to be dose-dependent if samples are collected over a short period or if they are assayed with a method of low sensitivity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00541305
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  • 249
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    Comparative effects of ranitidine and cimetidine on the pharmacokinetics and pharmacodynamics of warfarin in man (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 165-172 
    Details
    ISSN: 1432-1041
    Keywords: warfarin ; cimetidine ; ranitidine ; stereochemistry ; drug-drug interaction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Stereochemical aspects of the potential interaction between the oral anticoagulant warfarin and the H2-antagonists, cimetidine and ranitidine, were investigated. A single 25 mg oral dose of racemic warfarin was administered on Day 4 of a randomised 9-day multiple dosing regimen of either cimetidine (800 mg o.d.) ranitidine (300 mg o.d.) or placebo. The degree of anticoagulation produced by warfarin was quantificated by the determination of both the prothrombin and Factor VII clotting times. Ranitidine had no effect on the pharmacodynamics of warfarin or the pharmacokinetics of the individual warfarin enantiomers. Cimetidine whilst producing no statistically significant change in the pharmacodynamics of warfarin or in the pharmacokinetics of the pharmacologically more potent (S) enantiomer, did produce a statistically significant decrease in the clearance of the (R) enantiomer, possibly due to metabolic inhibition of this species.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542190
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  • 250
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    Pharmacokinetic interactions between felodipine and metoprolol (1987)
    Springer
    European journal of clinical pharmacology 31 (1987), S. 575-578 
    Details
    ISSN: 1432-1041
    Keywords: felodipine ; metoprolol ; pharmacokinetics ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary This double-blind, cross-over study in healthy male subjects evaluated the pharmacokinetics of felodipine and metoprolol given both separately and in combination. During three, five-day study periods, felodipine 10 mg b.d., metoprolol 100 mg b.d. and a combination of the two, were given in random order. There was at least a 7-day washout period between each pharmacokinetic study day. Plasma levels of unchanged felodipine and metoprolol were measured for 24 h after the last dose, on the 5th day of each treatment period. Eight subjects, aged 19–22 years, completed the study. Both felodipine and metoprolol, given alone and in combination, were well tolerated. None of the felodipine pharmacokinetic variables (tmax, Cmax, Cmin, AUC (0–12) and t1/2) changed significantly when felodipine and metoprolol were given in combination. Cmax and AUC (0–12) for metoprolol increased significantly when metoprolol and felodipine were combined, although tmax, Cmin and t1/2 for metoprolol remained unchanged. The changes in metoprolol pharmacokinetics induced by felodipine are small and unlikely to be clinically important.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00606633
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  • 251
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    Verapamil-induced changes in digoxin kinetics in cirrhosis (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 309-311 
    Details
    ISSN: 1432-1041
    Keywords: digoxin ; verapamil ; cirrhosis ; drug interaction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of a single low dose of verapamil (80 mg) on the serum levels of digoxin (single dose of 0.5 mg) was studied in 6 patients with hepatic cirrhosis and in 6 healthy volunteer controls. In the cirrhotic patients verapamil increased the peak serum level and the total AUC of digoxin by 98% and 32%, respectively. There was an associated 23% decrease in the renal digoxin clearance. In normal subjects only marginal alterations in digoxin kinetics were observed following verapamil administration. The results indicate that cirrhosis magnifies the influence of verapamil on digoxin kinetics.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00607580
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    Concentration of azapropazone in synovial tissues and fluid (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 303-307 
    Details
    ISSN: 1432-1041
    Keywords: azapropazone ; arthritis ; pharmacokinetics ; synovial fluid level ; synovial tissue level
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The concentration-time curves of azapropazone in synovial fluid and tissues have been studied in arthritic patients after an i.v. bolus (600 mg) and under steady-state conditions. Synovial fluid and tissue samples were taken intraoperatively 0.45–60 h after administration. The azapropazone concentrations in synovial fluid, synovial tissue and plasma were correlated. The levels in synovial fluid were usually lower than corresponding plasma levels. Under steady-state conditions azapropazone did not accumulate in synovial tissues.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00607579
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    Lack of interaction of ranitidine with amitriptyline (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 317-320 
    Details
    ISSN: 1432-1041
    Keywords: ranitidine ; amitriptyline ; drug interaction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The possibility of an interaction of ranitidine with amitriptyline was assessed by means of amitriptyline and nortriptyline plasma concentration measurements, blood pressure and pulse rate, digit symbol substitution, and visual analogue scales. Ranitidine had no effect on amitriptyline or nortriptyline concentrations. Responses recorded by the digit symbol substitution and visual analogue scale tests correlated with changes in concentrations of amitriptyline and nortriptyline in plasma. No effects on blood pressure or pulse rate were observed. We concluded that there was no effect of ranitidine on amitriptyline kinetics or response in the conditions of our study.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00607582
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  • 254
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    Factors affecting the pharmacokinetics of nifedipine (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 351-355 
    Details
    ISSN: 1432-1041
    Keywords: nifedipine ; cimetidine ; pharmacokinetics ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma pharmacokinetics of nifedipine and the formation of its metabolites have been studied in volunteers under conditions which would affect the activity of the cytochrome P-450 system. The pharmacokinetics of a 10-mg capsule of nifedipine were not significantly different between smokers and non-smokers of similar age. After pretreatment with cimetidine, which inhibits the activity of cytochrome P-450, the peak plasma concentration and area under the plasma-time concentration curve for nifedipine were increased by a mean 84%. In contrast, pre-treatment with ranitidine which has little effect on cytochrome P-450, did not significantly alter nifedipine pharmacokinetics. Smoking does not contribute significantly to the variability in nifedipine pharmacokinetics. However, the interaction between nifedipine and cimetidine, but not ranitidine, may be of clinical importance.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00543968
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  • 255
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    Inter- and intra-subject variability of nitrendipine and the effects of food (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 357-360 
    Details
    ISSN: 1432-1041
    Keywords: nitrendipine ; food intake ; pharmacokinetics ; variability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma concentrations of nitrendipine were measured, after single (20 mg) oral doses, in young healthy volunteers. On three occasions the subjects ingested the dose having fasted overnight. Data from these three occasions were used to assess variability in nitrendipine pharmacokinetics and both inter- and intra-subject variability were high. On a fourth occasion, the subjects took the tablet after a standard meal. The effects of food on nitrendipine pharmacokinetics, based on the comparison of data from the first fasting visit and the food visit, were negligible.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00543969
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    Kinetics of morphine in patients with renal failure (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 377-382 
    Details
    ISSN: 1432-1041
    Keywords: morphine ; renal failure ; pharmacokinetics ; morphine-3-glucuronide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of morphine and its glucuronidated metabolites were investigated in seven patients with advanced renal failure. The terminal elimination half life of morphine varied between 1.5 and 4.0 h (mean 2.4 h), the volume of distribution between 2.5 and 6.3 l·kg−1 (mean 4.4 l·kg−1) and the total plasma clearance between 13.3 and 31.3 l·min−1·kg−1 (mean 21.1 l·kg−1). There were no statistically significant differences between the pharmacokinetic data in the uraemic patients and in a control group of cancer patients with normal kidney function. The concentrations of the glucuronidated metabolites rapidly rose to levels above those of morphine. The elimination half-life of M3G varied between 14.5 and 118.8 h (mean 49.6 h) in the renal failure patients, which is distinctly different from the 2.4 to 6.7 h (mean 4.0 h) found in patients with normal kidney function. There was a significant correlation between the half-life of M3G and renal function estimated as serum urea. Thus, the metabolism of morphine in patients with kidney disease is not significantly impaired. The clinical importance of the high concentrations of glucuronides in uraemic patients is not known.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00543973
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  • 257
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    Non-linear elimination and protein binding of probenecid (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 395-401 
    Details
    ISSN: 1432-1041
    Keywords: probenecid ; Michaelis-Menten kinetics ; protein binding ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Six healthy volunteers were given probenecid 0.5, 1 and 2 g p.o. and 0.5 g i.v. The protein binding of probenecid at different concentrations in human plasma was estimated by equilibrium dialysis. The free fraction was found to increase nonlinearly with increasing total probenecid concentration, up to a maximum free fraction of 26%. The plasma concentration-time data after the oral doses were described by a one-compartment open model with first-order absorption and Michaelis-Menten elimination. The mean absorption rate constant 0.0072 min−1 was dose-independent, and the maximal rate of elimination (mean 1429 µg/min) did not differ between doses whether calculated from the total or free concentrations. The Michaelis-Menten constant decreased significantly from 67.1 to 55.5 µg/ml as the dose increased from 1 g to 2 g, while the unbound Michaelis-Menten constant remained unchanged. The elimination of probenecid after the 0.5 g dose was in the linear region of the Michaelis-Menten elimination when calculated from the total and the free concentrations. The volume of distribution increased only slightly from 9.5 to 11.4 l as the dose increased from 0.5 to 2 g, but the unbound volume of distribution decreased significantly from 164 to 99 l. Absorption was complete and was independent of the dose administered.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00543976
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    Inhibition and induction of metronidazole and antipyrine metabolism (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 35-41 
    Details
    ISSN: 1432-1041
    Keywords: metronidazole ; antipyrine ; cimetidine ; phenobarbitone ; drug interaction ; drug metabolism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of cimetidine, antipyrine and phenobarbitone on the pharmacokinetics of intravenous metronidazole and oral antipyrine has been examined in 7 healthy volunteers. The administration of cimetidine for 24 h before and throughout the sampling period failed to alter the total clearance of metronidazole or the rate of formation of the hydroxy metabolite, whereas the total and partial clearances of antipyrine were decreased 0.74 and 0.6–0.7-fold, respectively, Seven days of phenobarbitone or antipyrine administration increased the total clearance of metronidazole 1.51- and 1.86-fold, respectively, and the total antipyrine clearance was 1.22 or 1.46-fold increased, respectively. The rate of metronidazole hydroxylation was significantly enhanced by both enzyme inducers. The partial clearance of antipyrine to the normetabolite was significantly increased by both inducers, wheras the rate of 4-hydroxylation was significantly increased only by prior antipyrine administration. The results indicate that the hydroxylation of metronidazole is not inhibited by cimetidine, but that it is inducible by phenobarbitone or antipyrine. It is suggested that metronidazole and antipyrine are metabolized by different enzymatic pathways.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609955
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    Pharmacodynamics and pharmacokinetics of urapidil in hypertensive patients: A crossover study comparing infusion with an infusion-capsule combination (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 61-65 
    Details
    ISSN: 1432-1041
    Keywords: urapidil ; hypertension ; alpha-adrenoceptor blocker ; antihypertensive agent ; pharmacodynamics ; pharmacokinetics ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and haemodynamic effects of infused urapidil and an infusion-capsule combination were followed to study the correlation between the serum urapidil level and the blood pressure. Prior to urapidil administration, basal blood pressure and heart rate were measured for 16 h in 12 male hypertensive patients. Six patients received infusions lasting for 4 h of urapidil 10, 2.5 and 5 mg/h. Six patients were infused with urapidil 10 mg/h for 4 h and 2 h after the end of the infusion each took a 60-mg capsule. After a 5 day washout period the procedures were crossed over. A maximum serum urapidil level of 625±232 ng/ml was achieved at the end of the 10 mg/h infusion, when the fall in blood pressure was 37/21 mmHg. During the 2.5 and 5 mg/h infusions the serum urapidil level was 330 and 420 ng/ml, respectively, and the corresponding decreases in blood pressure were 28/16 mmHg and 31/8 mmHg. Although the urapidil concentration 1 hour after beginning the infusion was only 184±89 ng/ml a near maximal blood pressure decrease had already occurred 33±9/20±8 mmHg, whereas, 1 h after the end of the infusion the reduction in blood pressure was only 10±12/3±8 mm, with a urapidil concentration of 358±120 ng/ml. During the plateau phases of both the infusion and infusion-capsule treatments the falls in blood pressure followed the serum urapidil levels. Only in the initial rising and final falling phases of the treatments were the pharmacodynamics and pharmacokinetics of urapidil not correlated.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609958
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    The pharmacokinetics of single and multiple doses of tiaprofenic acid in elderly patients with arthritis (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 93-95 
    Details
    ISSN: 1432-1041
    Keywords: tiaprofenic acid ; arthritis ; pharmacokinetics ; elderly
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the single dose and steady-state pharmacokinetic of tiaprofenic acid in ten elderly arthritic patients living in the community (5 men and 5 women) taking 200 mg tid for 8 days. The mean area under the plasma concentration-time curves to 8 h (AUC (0–8)) did not alter significantly from day 1 to day 8 (77.25 to 79.61 µg·ml−1. h). The mean terminal phase half-life (t1/2) was 2.05 h and 2.25 h on Days 1 and 8 respectively in patients in whom the calculations were possible (7 patients on Day 1 and 6 patients on Day 8). The median observed time of maximum concentration (tmax) and the mean observed maximum plasma concentration (Cmax) of 100 min and 21.3 µg·ml−1 respectively on Day 1 were not significantly different from the values obtained on Day 8 (tmax 120 min; Cmax 20.7 µg·ml−1). The kinetic data suggest that there should be no significant accumulation of tiaprofenic acid in elderly ambulant people suffering from arthritis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609965
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  • 261
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    Pharmacokinetics of ornidazole in neonates and infants after a single intravenous infusion (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 111-113 
    Details
    ISSN: 1432-1041
    Keywords: ornidazole ; neonates ; pharmacokinetics ; intravenous infusion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The single dose pharmacokinetics of ornidazole has been evaluated in 12 neonates or infants (aged 1 to 42 weeks) after the infusion of 20 mg/kg over 20 min. Plasma disposition was described by a two-compartment open model. The distribution phase was short (T1/2 (1)=0.31 h) and was followed by an elimination phase (t1/2 (2)=14.67 h). The mean apparent volume of distribution was 0.96 l/kg−1. These results did not differ from data previous by reported in adults. Total plasma clearance was between 0.4 and 1.4 ml·min−1·kg−1. The plasma concentration 24 h after the infusion was 7.32 mg·l−1, which was above the minimum inhibitory concentration for clinically significant anaerobic bacteria. Based on the pharmacokinetic results and residual concentrations at 24 h, a single daily infusion of ornidazole 20 mg·kg−1 appears adequate for therapy in neonates and infants.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609970
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  • 262
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    Salicyl phenolic glucuronide pharmacokinetics in patients with rheumatoid arthritis (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 153-158 
    Details
    ISSN: 1432-1041
    Keywords: salicyl phenolic glucuronide ; rheumatoid arthritis ; aspirin ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of salicyl phenolic glucuronide (SPG) and other salicylic acid (SA) metabolites were studied at three aspirin dosage regimens in eight patients with rheumatoid arthritis. Each patient received 1, 2 and 4 g enteric coated aspirin (ASA) daily in ascending order. At the end of each 2-week dosage period, plasma and urine were collected over a dosage interval for the estimation of various pharmacokinetic parameters. With increasing ASA dosage, mean clearance of SA to SPG was approximately constant (1.8±0.3, 1.7±0.2, and 1.5±0.2 ml/min at 1, 2 and 4 g/day, respectively) when related to plasma concentrations of total SA. The percentage of the ASA dosage recovered in urine as SPG increased from 5.2±1.1 to 7.1±1.1 to 10.5±1.7 at 1, 2 and 4 g/day, respectively. It was concluded, however, that the conversion of SA to SPG is saturable, since the mean clearance of SA to SPG decreased when calculated with respect of the plasma concentration of unbound SA (13.4±1.6, 11.0±1.4, and 6.6±1.9 ml/min at 1, 2 and 4 g/day, respectively). The kinetics of the formation and excretion of salicylurate and the excretion of gentisate were similar to those found in previous studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542188
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    The influence of hypothermia on the disposition of fentanyl — Human and animal studies (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 373-376 
    Details
    ISSN: 1432-1041
    Keywords: hypothermia ; fentanyl ; pharmacokinetics ; cardiopulmonary bypass ; hypothermia-induced hypoperfusion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of hypothermia on the disposition of fentanyl was evaluated in 18 children undergoing corrective cardiac surgery. They received a bolus of fentanyl followed by a continuous infusion which was stopped when cardiopulmonary bypass was established and profound hypothermia was achieved (18 °C–25 °C). Fentanyl plasma concentration remained essentially unchanged during hypothermia (6.45 ng/ml 5 min into hypothermia and 5.26 ng/ml 100–140 min later; p〉0.1). In subsequent experiments, the effect of hypothermia on the pharmacokinetics of fentanyl was studied in 4 piglets serving as their own controls. Both distribution volume (Vz) and total body clearance (CL) were significantly smaller during hypothermia. Our studies indicate that being a drug with a large distribution volume and a high hepatic extraction ratio, both CL and Vz are significantly reduced by hypothermia-induced hypoperfusion. In addition, TBC is influenced by the temperature-dependent hepatic metabolism of fentanyl.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00543972
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  • 264
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    Pharmacokinetics of isosorbide-5-nitrate during haemodialysis and peritoneal dialysis (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 503-505 
    Details
    ISSN: 1432-1041
    Keywords: isosorbide-5-nitrate ; renal failure ; haemodialysis ; peritoneal dialysis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of isosorbide-5-nitrate (IS-5-N) was studied in ten patients on haemodialysis (HD) after a single oral dose of 20 mg IS-5-N, and in six patients on continuous ambulatory peritoneal dialysis (CAPD) after repeated oral doses of 3×20 mg IS-5-N. There was significant removal of IS-5-N from blood during HD; Cmax decreased by about 20%, AUC(0–8 h) by 30% and t1/2 by about 20% from 4.3 to 3.4 h, and plasma clearance was increased by 81 ml/min. No important loss of IS-5-N was observed in patients on CAPD.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00637678
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    The interaction of erythromycin with theophylline (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 493-498 
    Details
    ISSN: 1432-1041
    Keywords: theophylline ; erythromycin ; drug interaction ; aminophylline ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the interaction of erythromycin with theophylline. We gave ten healthy volunteers theophylline as an intravenous loading dose (5 mg·kg−1) over 1 h, followed by a maintenance infusion (0.5 mg·kg−1·h−1) for 5 h. A second infusion of theophylline was given after 9 days of treatment with 1 g erythromycin base daily, and the concentrations of theophylline were determined during the infusion periods. The concentrations of erythromycin were measured for 8 h, after one week of treatment, and also after the last erythromycin dose, simultaneously with the second theophylline infusion. Concentrations within the therapeutic range were obtained with both drugs. A significant increase in both AUC and mean plasma concentrations of theophylline was seen during erythromycin treatment. The plasma clearance of theophylline was reduced in 9 of the 10 subjects. Renal clearance increased correspondingly, but the change was not statistically significant. Serum concentrations of erythromycin fell significantly, by more than 30%, with concurrent theophylline medication. We conclude that an interaction between theophylline and erythromycin, affecting both drugs, can be shown with concentrations of the drugs within the therapeutic range.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00637676
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    Pharmacokinetics and absolute bioavailability of salbutamol in healthy adult volunteers (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 631-634 
    Details
    ISSN: 1432-1041
    Keywords: salbutamol ; albuterol ; pharmacokinetics ; bioavailability ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Salbutamol was administered to sixteen healthy male volunteers intravenously and by mouth in liquid, tablet, and capsule form using a Latin-Squares design. Pharmacokinetic parameters from intravenous data were similar to previously reported values obtained with oral administration, with a mean terminal half-life of 3.8 h and a mean clearance of 439 ml·min−1·1.73 m−2. Peak plasma concentrations of 10–20 ng·ml−1 were obtained 1–3 h following oral administration. The absolute bioavailability of each of the oral preparations was 44%. While statistically significant differences in lag time and time to peak concentration were noted among the various oral preparations, the drug is rapidly absorbed in all three dosage forms and the observed differences are unlikely to be of clinical significance.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02456001
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    Single oral dose pharmacokinetics of tiapride in patients with Huntington's disease (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 583-586 
    Details
    ISSN: 1432-1041
    Keywords: tiapride ; Huntington's disease ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic properties of a single oral dose of 100 mg of tiapride were studied in six patients with Huntington's disease. The results for five patients were consistent with a two compartment open model. Peak plasma concentrations were observed within 2 h following durg administration with a mean value of 0.92 μg/ml being recorded. The drug was rapidly eliminated as unmetabolised tiapride in the urine, 51% of the dose was recovered in 24 h. The plasma elimination half-life was 5.3 h and the average apparent plasma clearance was 16.6 l/h.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02455992
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    The pharmacokinetics of single high doses of dexamethasone in cancer patients (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 593-596 
    Details
    ISSN: 1432-1041
    Keywords: dexamethasone ; dexamethasone phosphate, antiemetic ; pharmacokinetics ; cancer chemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have given single high doses of dexamethasone phosphate by intravenous infusion as an antiemetic to 15 cancer patients receiving regimens containing cisplatin and/or doxorubicin. The patients received graded doses of dexamethasone phosphate, in the range 40–200 mg, dependent upon nausea and vomiting scores, during up to three consecutive cycles of cancer chemotherapy. Plasma and urine concentrations of dexamethasone (dexamethasone alcohol) were measured by HPLC. The plasma concentration-time data were described by an open two-compartment model. The pharmacokinetic variables were independent of the dose of dexamethasone over the range studied. The terminal half-time was 4.0±0.4 h and the total body clearance was 3.5±0.4 ml·min−1·kg−1. The volume of the central compartment and the total apparent volume of distribution were 0.23±0.03 and 1.0±0.1 l·kg−1 respectively. Approximately 8% of the dose was excreted into the urine as dexamethasone.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02455994
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    A modified pharmacokinetic model for platinum disposition in ovarian cancer patients receiving cisplatin (1987)
    Springer
    European journal of clinical pharmacology 33 (1987), S. 67-72 
    Details
    ISSN: 1432-1041
    Keywords: cisplatin ; pharmacokinetics ; modelling ; drug dispositions ; cancer patients
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have fitted a first-order multicompartment pharmacokinetic model to plasma platinum concentrations measured in nine ovarian cancer patients who received intravenous infusions of cisplatin for 6 h. The time-course of ultrafilterable plasma platinum was similar in all patients studied, and was fitted by a single compartment within the limits of experimental detection. However, the time-course of protein-bound platinum showed marked differences between patients, the differences being explained by distribution to two peripheral compartments. The wide inter-patient variation observed in protein-bound plasma platinum concentrations supports the view that pharmacokinetic modelling should be carried out separately for each patient, since averaging plasma concentrations would have obscured some individual pharmacokinetic characteristics.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00610382
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  • 270
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    The pharmacokinetics of indoramin and 6-hydroxyindoramin in poor and extensive hydroxylators of debrisoquine (1987)
    Springer
    European journal of clinical pharmacology 33 (1987), S. 59-65 
    Details
    ISSN: 1432-1041
    Keywords: indoramin ; 6-hydroxyindoramin ; debrisoquine ; hydroxylators ; genetic polymorphism ; blood pressure ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five poor metabolisers (PM) and seven extensive metabolisers (EM), of debrisoquine, all healthy volunteers, received 50 mg indoramin orally following an overnight fast. Plasma concentrations of indoramin and 6-hydroxyindoramin were determined by HPLC with fluorimetric detection. In PM subjects, mean values of Cmax (158 ng/ml) and AUC(0–24) (2556 ng·h·m−1) for indoramin were substantially elevated and t1/2β (18.5 h) prolonged by comparison with values in the EM subjects (21.6 ng/ml, 151 ng·h·ml−1 and 5.2 h respectively). For 6-hydroxyindoramin, on the other hand, Cmax (12.4 ng/ml) and AUC(0–8) (47.5 ng·h·ml−1) in PM subjects were significantly lower than in the EM subjects (28.2 ng/ml and 94.7 ng·h·ml−1). There was a tendency to a higher incidence of side-effects in the PM group. Although the difference did not achieve statistical significance (0.1〉p〉0.05), all the PM subjects experienced sedation compared to only two in the EM group. Differences in blood pressure and pulse rate between the two groups were small. It is concluded that the oxidative metabolism of indoramin is subject to genetic polymorphism, which is probably under the control of the same gene locus as that influencing debrisoquine oxidation. The clinical consequences are discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00610381
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    Predictability of serum concentrations of aminoglycosides after haemodialysis (1987)
    Springer
    European journal of clinical pharmacology 33 (1987), S. 179-183 
    Details
    ISSN: 1432-1041
    Keywords: aminoglycosides ; haemodialysis ; gentamicin ; tobramycin ; pharmacokinetics ; renal failure ; kanamycin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The study was undertaken to look for a correlation between the measured elimination rate constants (k) of aminoglycosides and creatinine during haemodialysis. The pharmacokinetics of aminoglycosides were studied during 44 courses of haemodialysis in 21 patients. The measured k of gentamicin and tobramycin from the start until 30 min after the end of haemodialysis (mean 0.18 h−1; t1/2=3 h 51 min) was significantly correlated with the measured k of creatinine (mean 0.13 h−1; t1/2=5 h, 20 min), and also with the gentamicin and tobramycin k during haemodialysis (mean 0.20 h−1, t1/2=3 h, 28 min), as predicted by a computer program. Thus, serum concentrations of aminoglycosides 30 min after haemodialysis can be estimated by simple regression equations. However, because the measured and predicted values may diverge considerably in the individual patient, monitoring of aminoglycoside concentrations in serum after haemodialysis remains necessary.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00544564
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    Penetration of praziquantel into cerebrospinal fluid and cysticerci in human cysticercosis (1987)
    Springer
    European journal of clinical pharmacology 33 (1987), S. 287-292 
    Details
    ISSN: 1432-1041
    Keywords: praziquantel ; cysticercosis ; pharmacokinetics ; cerebrospinal fluid ; parasite drug level
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Two patients with cysticercosis received praziquantel (PZQ) 75 mg/kg/day orally together with 30 mg prednisone daily for 3 weeks. The first patient presented with grand-mal seizures, a pyramidal tract syndrome and subcutaneous cysticerci, and the other had internal hydrocephalus necessitating drainage. Serial plasma samples were taken after the first dose of PZQ. Lumbar CSF was obtained from the first patient and ventricular CSF from the second. Subcutaneous cysticerci were removed from the first patient. PZQ in the specimens was assayed by GLC. For distribution between plasma and CSF a rate constant of 4.9 h−1 for free PZQ, corresponding to a t1/2 of 8 min or less for the non-protein bound fraction was calculated for Patient 1. In the second patient the distribution was so rapid that the rate constant could not be calculated. The difference in distribution rate might have been due to use of different sampling times or to a time lag in the entry of PZQ between the ventricles and the lumbar sac. The rate constant for distribution of the drug between plasma and parasites was 1.4 h−1, corresponding to a t1/2 of 30 min or less. Thus PZQ penetrates rapidly into the CSF. It enters the parasite more slowly, although still more rapidly than the plasma half-life of PZQ (1–1 1/2 h).
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    URL: http://dx.doi.org/10.1007/BF00637564
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    Disposition of the adrenergic blocker metoprolol and its metabolite OH-metoprolol in maternal plasma, amniotic fluid and capillary blood of the neonate (1987)
    Springer
    European journal of clinical pharmacology 33 (1987), S. 363-368 
    Details
    ISSN: 1432-1041
    Keywords: metoprolol ; neonates ; amniotic fluid ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Seven women were treated with metoprolol 50–100 mg twice daily for hypertension in pregnancy. The disposition of metoprolol and one of its metabolites alfa-OH-metoprolol was studied in venous plasma and amniotic fluid during labour, in mixed cord plasma and in capillary blood of the newborn. Peak concentrations of metoprolol and alfa-OH-metoprolol were reached 60 to 120 min after dosing in maternal plasma while the amniotic fluid levels of these compounds continued to increase from 60 to 180 min to the end of the study and were substantially higher than in the plasma after 4 to 5 h. It is postulated that a major fraction of metoprolol and alfa-OH-metoprolol reaches the amniotic fluid via the fetal urine and that the elimination from the amniotic fluid mainly proceeds via diffusion across fetal membranes and transfer across the fetal capillary bed. No measurable concentrations of metoprolol were found in two of the newborns 2 h after delivery. In the remaining four neonates the 2-h concentrations exceeded the corresponding cord plasma levels. In all neonates the alfa-OH-metoprolol levels in the capillary blood were higher 2 h after birth than in cord blood. In two newborns the metabolite levels continued to increase for 5 h and in one the highest blood concentrations of this metabolite was found 20 h after birth. Redistribution of metoprolol from tissue stores followed by metabolism might be the cause of these temporary elevations of the blood levels of metoprolol and alfa-OH-metoprolol.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00637631
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    Pharmacokinetics of phenylethylmalonamide (PEMA) in elderly men (1987)
    Springer
    European journal of clinical pharmacology 33 (1987), S. 431-434 
    Details
    ISSN: 1432-1041
    Keywords: phenylethylmalonamide ; pharmacokinetics ; elderly
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of phenylethylmalonamide (PEMA) were studied in 6 elderly men after oral administration of a single 400 mg dose. Peak PEMA serum levels were obtained within 4 h of intake, half-life values ranged from 30.7–57.9 h in these elderly men. The elimination half-life was twice as long when compared to a study previously performed in young volunteers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00637644
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    Pharmacokinetics of amiloride in renal and hepatic disease (1987)
    Springer
    European journal of clinical pharmacology 33 (1987), S. 493-498 
    Details
    ISSN: 1432-1041
    Keywords: amiloride ; pharmacokinetics ; renal failure ; liver disease ; urinary excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of the antikaliuretic amiloride has been studied in healthy controls and in patients with chronic renal failure or hepatitis. It was 40% bound to protein. In healthy volunteers 49% of an oral dose was recovered unchanged in the urine. The renal clearance of amiloride was about 3 times the creatinine clearance, which means that it was predominantly excreted via tubular secretion. Renal impairment reduced the clearance of amiloride, causing a prolongation of the t1/2 and drug accumulation in plasma. In hepatitis the t1/2 of amiloride was prolonged and the AUC increased. Urinary recovery (Ae) of amiloride was greater in hepatitis patients than in controls.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00544242
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    Pharmacokinetics of different epidural sites of morphine administration (1987)
    Springer
    European journal of clinical pharmacology 33 (1987), S. 499-504 
    Details
    ISSN: 1432-1041
    Keywords: morphine ; epidural administration ; pharmacokinetics ; CSF/plasma concentrations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In order to determine the rate and degree of redistribution of morphine within the cerebrospinal fluid (CSF), and whether it was affected by the site of and volume of the injection, morphine was given to 23 elderly patients undergoing thoracotomy — in 10 ml saline in the lumbar epidural interspace (n=5), in 10 ml saline in the thoracic epidural interspace (n=5), in 2 ml saline in the thoracic interspace (n=8) and in 10 ml saline in the lumbar epidural interspace (n=5). The plasma concentration of morphine in all patients was comparable and was much lower than in the CSF. The CSF morphine concentration, measured as the area under the CSF concentration curve (AUC), the maximal CSF concentration (Cmax) and the time to reach maximal CSF concentration (tmax), varied between the four groups. The variation was related to the site of the injection; the AUC and Cmax were lower and tmax appeared later after thoracic than lumbar injection. Lumbar CSF morphine concentrations were further reduced by thoracic epidural injection of morphine in a small as compared to a large volume. The permeability of the dura to morphine was not influenced by the volume used. The results show that morphine is not homogenously distributed within the CSF. The availability of morphine to CSF from the epidural space is not altered by the injection volume, but the drug remains more localized in CSF after epidural injection of morphine in a small volume. The findings imply that epidural injection of morphine in a small volume at a site of nociceptive input should evoke spinal analgesia with least risk of supraspinally mediated side effects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00544243
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    Treatment of persistent fetal circulation syndrome of the newborn. Comparison of different doses of tolazoline (1987)
    Springer
    European journal of clinical pharmacology 31 (1987), S. 569-573 
    Details
    ISSN: 1432-1041
    Keywords: tolazoline ; neonates ; persistent fetal circulation ; pharmacodynamic effects ; pharmacokinetics ; pulmonary circulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of two doses of tolazoline have been compared in 2 groups of newborns suffering from the persistent fetal circulation syndrome. The effects on PaO2 and AaDO2 were similar in the 2 groups who received either a bolus of 1 or 0.5 mg·kg−1 tolazoline, followed by a continuous infusion of 1 or 0.5 mg·kg−1·h−1. The observed changes did not differ significantly from those previously observed in babies treated with 2 mg·kg−1. A rise in PaO2 and a reduction in AaDO2 were usually observed shortly after the bolus injection and at plasma levels between 1.5 and 4 µg·ml·−1. A progressive rise in plasma level over time occurred after 1 mg·kg−1 (and in the previous study of 2 mg) but not with 0.5g/kg tolazoline. The elimination half-life of tolazoline in 6 patients was 5 to 13 h. The data suggest that continuous infusion of tolazoline is not necessarily required and that the dose of 0.5 mg/kg is more appropriate and safer than the higher doses usually proposed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00606632
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    Pharmacokinetics of enprofylline in healthy elderly subjects (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 67-70 
    Details
    ISSN: 1432-1041
    Keywords: enprofylline ; pharmacokinetics ; elderly ; renal excretion ; half-life
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of enprofylline, a new potent antiasthmatic, has been studied in 20 healthy, elderly subjects, aged 65 to 81 years, and in 7 young adult controls, aged 23 to 37 years. The dose of 1 mg/kg body weight was given as an i.v. infusion. Plasma levels of enprofylline were followed for about 7 h and urine levels for 24 h. Both groups eliminated the major portion of the dose (about 83%) by renal excretion. As expected the mean creatinine clearance (92.5 ml·min−1· 1.73 m−2) was moderately decreased in the elderly subjects. The total clearance of enprofylline was 0.16 1·h−1·kg−1 and the renal clearance was 0.13 l·h−1·kg−1, which was significantly lower than that in the young controls (0.28 and 0.22 l·h−1·kg−1) respectively. Thus, the enprofylline clearance had fallen relatively more (about 40%) than the decrease in creatinine clearance (about 20%) with age. The half-life of enprofylline in old age was 2.5 h, which was significantly longer than in the younger adults (1.8 h). It is concluded that the pharmacokinetics of enprofylline was significantly influenced by advanced age, mainly due to reduced renal excretion. This reduction was more pronounced than anticipated from the age-dependent decline in creatinine clearance.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609959
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  • 279
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    Effect of concomitant food intake on absorption kinetics of fenoldopam (SK&F 82526) in healthy volunteers (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 103-106 
    Details
    ISSN: 1432-1041
    Keywords: fenoldopam ; peripheral dopamine agonist ; pharmacokinetics ; absorption ; food effects ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Eight healthy volunteers participated in an open crossover study to assess the effect of a standardised meal on the systemic availability of a single oral dose of fenoldopam mesylate 100 mg. Subjects were studied on four separate occasions, twice fasting and twice fed in randomised, balanced order. Plasma and urine samples were obtained before and at regular intervals up to 25 h post dose. Measurement of fenoldopam (SK&F 82526) and its 8-sulphate metabolite (SK&F 87782) were by means of HPLC-EC analysis. Area under the plasma concentration time curve (AUC) and maximum detected plasma concentration (Cmax) for fenoldopam and SK&F 87782 were significantly reduced whereas time to maximum concentration was significantly increased with food. Using AUC's for fenoldopam and SK&F 87782, mean relative bioavailabilities were 35% and 81% respectively under fed compared with fasting conditions. Twenty-four hour excretion of fenoldopam was significantly reduced with food, but excretion of SK&F 87782 was apparently unchanged. Mean relative bioavailabilities calculated from these data were 83% and 86% respectively. Relatively large inter-subject variability in AUC and Cmax were seen, but intra-subject variability was not marked. Mild symptoms associated with vasodilation were reported on all study days.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609968
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  • 280
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    The pharmacokinetics of mefloquine when given alone or in combination with sulphadoxine and pyrimethamine in Thai male and female subjects (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 173-177 
    Details
    ISSN: 1432-1041
    Keywords: mefloquine ; mefloquine/sulphadoxine/pyrimethamine ; Thai subjects ; pharmacokinetics ; drug interactions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of mefloquine were studied in 12 healthy Thai male and 12 healthy Thai female volunteers. Mefloquine (MQ) was administered either alone (750 mg orally) or in combination (MSP) with sulphadoxine (1.5 g) and pyrimethamine (75 mg) to each of 6 male and 6 female subjects. Plasma concentrations of MQ were measured by HPLC at intervals for 42 days. There was considerable interindividual variability in the pharmacokinetic parameters; for example in the male subjects receiving MQ alone peak concentrations ranged between 638 and 2494 ng·ml−1 with a mean concentration of 1442 ng·ml−1. Compared to previously published data on MQ concentrations in Caucasian male subjects, the present study indicates that higher concentrations are achieved in Thai subjects. The only significant difference in kinetic parameters between male and female subjects receiving MQ alone was in the mean residence time (MRT) which was greater in females. However, an analysis of pharmacokinetic parameters following administration of the combination preparation showed that the time to peak (tmax) was significantly reduced in females receiving MSP compared to the corresponding females given MQ alone and males given MSP. When data obtained from all subjects (male and female) receiving either MQ alone or MSP were combined, both MRT and half-life were significantly greater in subjects given MSP. There is therefore some evidence that therapeutic concentrations of MQ are maintained for a longer period of time following MSP administration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542191
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  • 281
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    Melphalan concentration dependent plasma protein binding in healthy humans and rats (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 179-185 
    Details
    ISSN: 1432-1041
    Keywords: melphalan ; protein binding ; plasma ; humans ; rats ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The binding of melphalan to plasma proteins from four healthy humans and from rats was measured by centrifugal ultrafiltration. Melphalan concentrations were determined by HPLC and by measuring 14C-melphalan activity. In whole blood, melphalan was distributed preferentially in plasma. However, a constant fraction, 37%, which was independent of the total melphalan concentration in whole blood, was present within the red blood cells. The binding of melphalan to plasma proteins from humans was less than that from rats. In both, however, the fraction bound was constant throughout the concentration range (0.1 to 9.0 µM) that is achieved during standard-dose melphalan therapy. Albumin was the primary binding protein. At concentrations equal to or in excess of 33 µM, which have been achieved during high-dose melphalan therapy, free plasma melphalan concentrations were no longer linearly related to total drug concentrations, and the plasma protein binding of melphalan in the human became concentration dependent. This occurred at concentrations of 70 µM in the rat. Scatchard analysis of the data indicated the presence of 2 groups of binding sites. Class I sites had 0.03 and 0.4 binding sites per albumin molecule in humans and rats, with respective association constants of 4.43 × 104M−1 and 1.92 × 104M−1. Class II sites had 5.18 and 2.60 binding sites per molecule, with repective association constants of 3.82 × 102M−1 and 2.01 × 102M−1.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542192
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  • 282
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    Single dose primaquine has no effect on paracetamol clearance (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 203-205 
    Details
    ISSN: 1432-1041
    Keywords: paracetamol ; primaquine ; drug interaction ; metabolite formation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of paracetamol and the formation of metabolites were evaluated in 6 healthy volunteers before and during concomitant administration of a single dose (45 mg) of primaquine. There was no effect of the antimalarial drug on either conjugation (to paracetamol glucuronide and paracetamol sulphate) or oxidation (as judged by the presence of paracetamol cysteine and paracetamol mercapturate) pathways. Although primaquine inhibits certain oxidative metabolism (e.g. of antipyrine) it has no effect, in therapeutic doses, on paracetamol metabolism.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542197
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  • 283
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    Differences in diazepam pharmacokinetics in Chinese and white Caucasians – Relation to body lipid stores (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 211-215 
    Details
    ISSN: 1432-1041
    Keywords: diazepam ; pharmacokinetics ; Chinese ; white Caucasians ; body fat ; skin-fold thickness
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have compared diazepam pharmacokinetics in 16 Chinese and 18 white Caucasian healthy male volunteers, resident in Hong Kong and have correlated them with physical attributes. Serum concentrations of diazepam and desmethyldiazepam were measured in venous blood by an enzyme-linked immunoassay (0–3 h samples) and HPLC (3–72 h samples). Pharmacokinetic parameters were derived assuming a two compartment model, distribution phase 〈6 h, and 100% oral systemic availability. Compared with the Chinese the white Caucasians were older, heavier, taller, and fatter, as judged by skin fold thickness (SFT) and total body weight to ‘Ideal’ body weight (TBW/IBW) ratio; respective mean differences being 16%, 27%, 4%, 26%, and 15% (p〈0.05). Mean diazepam apparent volume of distribution (V) and V/IBW were larger in the white Caucasians (52% & 39% respectively, p=0.002). SFT and TBW/IBW ratio yielded the best correlations with V, V/TBW and V/IBW (0.50–0.75, p〈0.05). Obesity indices contributed most to the overall regressions (R2 up to 0.52), and for V there was a further small effect (2%, partial F test) due to ethnic group, possibly reflecting stature. Mean peak diazepam concentration (Cmax) was similar in both ethnic groups. Time to Cmax (tmax) was more often prolonged in the Chinese (X 2 test, p=0.01). Body fat and stature may thus account for these inter-ethnic differences in the apparent volume of distribution of diazepam, a highly lipid-soluble drug.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542199
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    Pharmacokinetics of ketanserin in patients with essential hypertension (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 259-265 
    Details
    ISSN: 1432-1041
    Keywords: ketanserin ; ketanserin-ol ; pharmacokinetics ; hypertension
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of ketanserin and its main metabolite ketanserin-ol, and the antihypertensive effects of intravenous, single oral and chronic oral (40 mg once daily) administration of ketanserin, have been investigated in a single blind study of 10 patients with uncomplicated mild hypertension. Ketanserin had a terminal half-life of 29.2 h, a plasma clearance of 518 ml/min and a volume of distribution of 18.0 l/kg. Chronic oral intake of 40 mg ketanserin (tablet formulation) gave a peak concentration of unchanged ketanserin of 88 ng/ml after 1.1 h. Its absolute bioavailability was 48%. During chronic therapy the maximal concentration of ketanserin-ol was 208 ng/ml and its half-life of elimination was 35.0 h. As this metabolite can be oxidized back to ketanserin, it contributes to the prolonged half-life of unchanged ketanserin seen during chronic therapy. The blood pressure was reduced by approximately 15% by oral ketanserin. The maximal reduction in blood pressure coincided with the peak concentration of unchanged ketanserin. During chronic therapy with 40 mg once daily blood pressure was reduced over 24 h. The heart rate was slightly reduced and the cardiovascular responses and the plasma noradrenaline concentrations during isometric exercise were only slightly influenced by ketanserin therapy. Thus, unchanged ketanserin has a relatively long half-life during chronic oral therapy and its pharmacokinetics in middle-aged hypertensive patients is similar to that in normal young volunteers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00607573
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    Longitudinal effects of pregnancy on the pharmacokinetics of theophylline (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 289-295 
    Details
    ISSN: 1432-1041
    Keywords: theophylline ; pregnancy ; pharmacokinetics ; lactation ; methylxanthines ; metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of pregnancy on the disposition of theophylline were assessed in 10 patients throughout pregnancy and post-partum. The clearance relative to total theophylline concentrations was only slightly affected during the first two trimesters (2.61±0.63 l/h and 2.85±1.05 l/h), while a statistically significant reduction was evident late in pregnancy (2.05±0.49 l/h). Post-partum clearance values (2.16±2.81 l/h) suggest an ongoing suppression relative to pre-pregnancy levels. A similar pattern was evident with clearance values based on free theophylline plasma concentrations (p=0.12). Absolute volume of distribution increased in concert with gestation, suggesting that theophylline partitions into the enlarged tissue spaces. In addition, theophylline binding to plasma proteins decreased, albeit insignificantly, during the second (fraction bound=29%) and third (32%) trimesters compared to post-partum values (41%). Increases in half-life during the third trimester (13.00±2.31 h vs 9.53±3.53 h post-partum) were highly significant. This change reflects the net effect of reduced clearance and increased distribution. Breast feeding had no effect on the disposition of theophylline, although the transfer of this compound into breast milk was confirmed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00607577
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  • 286
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    Nonlinear pharmacokinetic characteristics of 5-fluorouracil (5-FU) in colorectal cancer patients (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 411-418 
    Details
    ISSN: 1432-1041
    Keywords: 5-fluorouracil ; colorectal carcinoma ; pharmacokinetics ; product-inhibition ; blood clearance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The nonlinear disposition kinetics of 5-fluorouracil (5-FU) were investigated in 6 patients with colorectal carcinoma. Each patient randomly received two single, intravenous doses of 5-FU (7.5 and 15 mg/kg) on separate days. Venous blood and urine samples were collected just prior to and for 5 h after drug administration. In addition to the kinetic studies, the in vitro whole blood/plasma concentration ratio and stability of 5-FU at 37°C were determined in whole blood from normal volunteers and from 5 patients with colorectal carcinoma. A disproportionate increase in area under the curve and corresponding decrease in total body clearance with increasing dose was observed suggesting dose-dependent behavior of 5-FU. Doubling the dose was accompanied by a 36% decrease in nonrenal clearance but no apparent change in renal clearance. Therefore, the mechanism for dose-dependent elimination appears to be primarily associated with nonrenal processes. The mean 5-FU half-life following the high dose was nearly twice as long as that observed for the low dose (12.3 versus 6.2 min). The log-linear decline in plasma concentrations and increase in half-life with dose suggest the potential role of product-inhibition as an explanation for the observed nonlinearity in 5-FU elimination. The present study demonstrates that 5-FU degrades when incubated in whole blood. This most likely reflects metabolism in red blood cells or other blood-formed elements since 5-FU was stable in plasma. Although degradation in whole blood occurs, the estimated whole blood clearance does not contribute significantly to the observed total body clearance value. These findings suggest the possibility of pulmonary clearance of 5-FU.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00543978
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    Comparative pharmacokinetics of theophylline following two fluoroquinolones co-administration (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 431-432 
    Details
    ISSN: 1432-1041
    Keywords: theophylline ; fluoroquinolones ; drug interaction ; pharmacokinetics ; ofloxacin ; norfloxacin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Pretreatment for 3 days with oral ofloxacin or norfloxacin had no significant effect on the disposition of a single i.v. dose the theophylline in healthy volunteers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00543982
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    Pharmacokinetics of human growth hormone releasing factor (hGRF-44 NH2) in normal men after intravenous administration of a large range of doses (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 507-513 
    Details
    ISSN: 1432-1041
    Keywords: growth hormone releasing factor ; radio-immunoassay ; pharmacokinetics ; variance model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Three ranges of doses of growth hormone releasing factor (2.5–80 µg, 80–320 µg and 75–600 µg) were intravenously administered to healthy young volunteers in three double blind studies. Serum circulating GRF levels were determined by radioimmunoassay. Experimental concentration curves were fitted, using the extended least squares method, to a biexponential model for the structural model and power function for the variance model. The power variance model, compared to the constant variance model greatly reduced the coefficient of variation of the biexponential parameters. The power of the variance model was estimated to be 1.95. The distribution half-life was 6.6 min and the elimination half-life was 39.0 min (harmonic means). Total clearance was 0.12±0.01 µg/l/min. No difference between these parameters was found for the various doses. GRF kinetics was linear established in the range 10 to 600 µg which means that elimination was not altered by the increased doses.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00637679
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    Bioavailability and elimination of nitrendipine in liver disease (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 563-568 
    Details
    ISSN: 1432-1041
    Keywords: nitrendipine ; pharmacokinetics ; hepatitis ; liver cirrhosis ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Twenty one patients with liver disease (cirrhosis 11, chronic hepatitis 5 and acute hepatitis 5) and 6 healthy volunteers were given a single i.v. dose of nitrendipine 5 mg. Afterwords nitrendipine 20 mg once daily were administered orally for seven days. With the intravenous injection a significant increase in the AUC and elimination half-life of nitrendipine was found in patients with cirrhosis as compared to the normal volunteers. After chronic oral dosing, the area under the plasma concentration-time curve, AUC (0–24), was 94.5 ng ml−1 h and the plasma clearance CL was 1380.6 ml/min in the healthy controls; in patients with cirrhosis the AUC (0–24) h was significantly greater at 309.4 ng ml−1 h and CL had fallen to 686.6 ml/min. Considerable accumulation of nitrendipine was also found in the patients with chronic hepatitis. Nitrendipine could not be detected in urine from any of the subjects. Blood pressure and heart rate were not significantly influenced by the treatment in the various groups investigated. Antipyrine clearance in the patients with cirrhosis was correlated with the nitrendipine plasma clearance. Thus, accumulation of nitrendipine has been demonstrated in the patients with cirrhosis and chronic hepatitis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02455989
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    Pharmacokinetics and pharmacodynamics of radio-labeled iloprost in elderly volunteers (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 597-605 
    Details
    ISSN: 1432-1041
    Keywords: iloprost ; prostacyclin analogue ; pharmacokinetics ; pharmacodynamics ; radiolabeled study ; volunteers ; side-effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma levels and excretion of tritium-labeled iloprost in healthy elderly male and female volunteers have been measured after i.v. infusion of 2 ng·kg−1·min−1 for 4 h and oral administration of 0.1 and 0.48 μg/kg. During infusion, a steady-state of labeled compounds in the plasma was not achieved. Total radioactivity declined from a mean of 408 pg equiv/ml in three phases, with half-lives of 24 min, 1.7 h and 5.0 h, respectively. A steady-state of unchanged iloprost was reached rapidly with a peak of 81 pg/ml. Plasma levels declined biphasically with half-lives of 6 min and 31 min. Total clearance was 24 ml· min−1·kg−1. Maximum concentrations of labeled substances after oral administration were 307 and 1,051 pg equiv/ml after 29 and 39 min respectively. The peak of unchanged iloprost (116 pg/ml) was observed 7.5 min after an oral dose of 0.48 μg/kg. Bioavailability was 16%. Iloprost was totally metabolized and the metabolities were mainly excreted in urine. The main biotransformation products in plasma and urine were tentatively identified by cochromatography as dinor-and tetranoriloprost and their glucuronides. ADP-induced platelet aggregation was reduce by 60% during the i.v. infusion and 15 min after oral administration of 0.48 μg/kg. Heart rate and blood pressure were virtually unaffected. Common side-effects were facial flush, headache and nausea.
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    URL: http://dx.doi.org/10.1007/BF02455995
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    Bioavailability of disopyramide in normal volunteers using unbound concentration (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 625-629 
    Details
    ISSN: 1432-1041
    Keywords: disopyramide ; bioavailability ; saturable binding ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of disopyramide were determined in 10 healthy volunteers after a 300 mg oral dose and again after a 2mg/kg i.v. dose. The unbound clearance was 599 ml/min and the unbound renal clearance 310 ml/min. The terminal elimination rate constant of unbound drug was 0.180 h−1 after the i.v. dose and 0.203 h−1 after the oral dose. The absorption rate constant was 0.53−1 and the maximum peak concentration occurred after 3.2 h. The bioavailability was 0.809 using the area under the unbound plasma concentration time curve. Although a saturable plasma protein binding was found in all subjects the bioavailability using the total concentration, in contrast to theoretical expectations, showed the same value (0.813) as the unbound concentrations.
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    URL: http://dx.doi.org/10.1007/BF02456000
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    Kinetics of ceftazidime during plasmapheresis (1987)
    Springer
    European journal of clinical pharmacology 33 (1987), S. 197-201 
    Details
    ISSN: 1432-1041
    Keywords: ceftazidime ; renal impairment ; plasmapheresis ; pharmacokinetics ; cephalosporins ; autoimmune disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of plasmapheresis (PA) on the elimination kinetics of ceftazidime (Cef) has been investigated. A single dose of Cef was administered intravenously to 11 patients with autoimmune diseases and varying degrees of renal impairment (Group I CLCR〈50 ml/min, Group II CLCR〉50 ml/min). In Groups I and II the mean total clearance of Cef (CL) was 30 and 116 ml/min−1, respectively. The elimination half-life (t1\2β) and the volume of distribution (V) were significantly higher in Group I than in Group II (11.9 vs 2.0 h, 27.1 vs 18.5 l). PA had no influence on the plasma level-time profile of Cef. The amount of Cef recovered from separated plasma accounted for only 2 to 9% of the administered dose, being particularly low in patients with normal renal function (4.6%). Thus, since elimination of Cef via PA is negligible, dosage calculations should be based solely on renal function.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00544567
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    Enoxacin — a potent inhibitor of theophylline metabolism (1987)
    Springer
    European journal of clinical pharmacology 33 (1987), S. 227-230 
    Details
    ISSN: 1432-1041
    Keywords: enoxacin ; theophylline ; drug interaction ; healthy volunteers ; adverse effects ; pharmacokinetics ; renal tubular excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The mechanism of the theophylline-enoxacin interaction has been studied in six healthy subjects. Theophylline 250 mg was administered p.o., twice daily for 11 days in a sustained release dosage form. On the 4th day of treatment, blood samples were taken every 2 h and urine was collected over 1 dose interval. From Days 5 to 11 coated tablets of enoxacin 400 mg b.i.d. were coadministered. On Day 11 blood and urine were collected as on Day 4. The mean plasma theophylline concentration rose from 4.4 to 15.1 mg/l, corresponding to a 73.6% reduction in total clearance. The urinary excretion of unchanged theophylline increased from 12.7 to 35.3%, whereas the production of metabolites was reduced (1-demethylation 81.4%; 3-demethylation 83.1%, 8-hydroxylation 74.6%). The results indicate that the theophylline-enoxacin interaction may be due to inhibition of the cytochrome P-450 isozymes responsible for theophylline metabolism. Unexpectedly, the renal clearance of theophylline metabolites was found to be drastically reduced when enoxacin was coadministered. This led to unchanged or even to elevated plasma levels of the metabolites. The mechanism of this interaction is still to be elucidated, but it may be due to competition for renal tubular secretion.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00637553
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    Effect of iron deficiency anaemia and its treatment on sulphadimidine absorption (1987)
    Springer
    European journal of clinical pharmacology 33 (1987), S. 323-325 
    Details
    ISSN: 1432-1041
    Keywords: iron deficiency anaemia ; sulphadimidine ; absorption ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of iron deficiency anaemia and its treatment on the absorption of sulphadimidine has been investigated in adult patients. The absorption judged by total % of the dose excreted in urine and Cmax, tmax, AUC and Kabs in plasma, was not significantly different before and after iron therapy or correction of anaemia. However, sulphadimidine absorption by the anaemic patients was significantly greater than in normals.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00637571
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    Propranolol pharmacokinetics and pharmacodynamics after single doses and at steady-state (1987)
    Springer
    European journal of clinical pharmacology 33 (1987), S. 315-318 
    Details
    ISSN: 1432-1041
    Keywords: propranolol ; pharmacodynamics ; pharmacokinetics ; beta-blockade ; sustained-release propranolol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The duration and extent of cardiac beta-blockade and their relationship to propranolol pharmacokinetics were assessed in nine healthy volunteers. Each subject received 160 mg of regular propranolol (R), 160 mg of sustained-release propranolol (SR) and no drug (control), both as single doses and once daily for 7 days. After single doses and at steady-state, both products caused a decrease in exercise heart rate for at least 24 h, compared to control. The time course of effect was similar to the time course of serum propranolol concentration. The oral clearance of propranolol decreased from single doses to steady-state for both R and SR; however, the difference achieved statistical significance only for R. These changes were reflected in mean accumulation ratios (AUC steady-state 0–24 h/AUC single dose 0-infinity) of 1.49 and 1.68 for R and SR, respectively. The pharmacokinetic data are consistent with a decrease in intrinsic hepatic clearance of propranolol, leading to an increase in bioavailability at steady-state. Despite a two-fold difference in the bioavailability of R and SR, there was no difference in the area under the effect-time curve at steady-state.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00637569
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  • 296
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    Influence of smoking and gender on the disposition kinetics of metoprolol (1987)
    Springer
    European journal of clinical pharmacology 33 (1987), S. 355-361 
    Details
    ISSN: 1432-1041
    Keywords: metoprolol ; smoking ; gender ; pharmacokinetics ; HPLC ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The purpose of this study was to examine the influence of cigarette smoking and gender on the pharmacokinetics of metoprolol. Eighteen volunteers with no evidence of clinical disease each randomly received the following doses of metoprolol tartrate: 100 mg orally, 200 mg orally and 20 mg as a constant-rate intravenous infusion over 20 min. The only significant difference between smokers (S) and nonsmokers (NS) was that S had a larger steady-state volume of distribution (3.3 vs 2.5 l/kg). There were no differences in half-life, systemic clearance or bioavailability (f). No differences were observed between males (M) and females (FM) for any of the kinetic parameters examined. Systemic bioavailability varied markedly between subjects (range: 15 to 92%). In fifteen of the eighteen subjects, f was higher after the 200-mg dose compared to the 100-mg dose. These results suggest that metoprolol may be subject to saturable presystemic elimination and extend the previous observations of Johnsson et al. [1] who showed that f increased from 31% to 46% when doses were increased from 20 to 100 mg. However, the difference in f as the dose is increased is unlikely to be clinically significant since the mean difference is smaller than the variation in f among subjects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00637630
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  • 297
    Electronic Resource
    Electronic Resource
    Disposition of monodesethylamodiaquine after a single oral dose of amodiaquine and three regimens for prophylaxis againstPlasmodium falciparum malaria (1987)
    Springer
    European journal of clinical pharmacology 33 (1987), S. 409-414 
    Details
    ISSN: 1432-1041
    Keywords: amodiaquine ; Plasmodium falciparum malaria ; monodesethylamodiaquine ; HPLC ; pharmacokinetics ; prophylaxis ; metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition of monodesethylamodiaquine was studied in four healthy subjects after a single oral dose of 10 mg/kg amodiaquine base. Amodiaquine was not found in any sample, but the major metabolite monodesethylamodiaquine was detected and was assumed to be the sole derivative that contributed significantly to antimalarial activity in the blood. The best fit for the decay of the metabolite was obtained with a three-compartment model. The half-lives of the first two phases were 3.2 to 11.4 h for t1/2α1 and 22.7 to 50.3 h for t1/2α2 in plasma. The half-life of the terminal phase ( t1/2β) was between 9 and 18.2 days. The concentration in whole blood was 4- to 6-times higher than in plasma. Three schedules (alternate days, weekly, daily) of the conventional prophylactic dose of 10 mg/kg per week were compared in six other healthy subjects. There were significant differences in the plasma monodesethylamodiaquine levels between the three schedules.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00637639
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  • 298
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    Electronic Resource
    The pharmacokinetics of ketanserin after a single dose and at steady-state in hypertensive subjects (1987)
    Springer
    European journal of clinical pharmacology 33 (1987), S. 423-426 
    Details
    ISSN: 1432-1041
    Keywords: Ketanserin ; pharmacokinetics ; hypertension ; ketanserinol ; predicted plasma concentration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacokinetics of ketanserin in 6 hypertensive patients after a single oral 40 mg dose and at steady-state after 4 weeks treatment with 20 mg and then 40 mg 12-hourly. Pharmacokinetic variables after a single dose were similar to those reported in healthy volunteers, with median values for Cmax 112 ng·ml−1, tmax 1 h, and t1/2 19 h. The corresponding values for the metabolite ketanserinol were Cmax 155 ng·ml−1, tmax 2 h, and t1/2 25 h. The median AUC was 3.3 times greater for ketanserinol than for the parent drug. These results were used to predict the mean steady-state plasma concentrations of ketanserin and ketanserinol. Predicted values were on average similar to those observed after four weeks treatment with 40 mg 12-hourly, although there were marked differences between the observed and predicted values in some patients. There was no evidence of time- or dose-dependent kinetics for ketanserin, but the study had insufficient power to exclude the occurrence of these phenomena entirely.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00637642
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  • 299
    Electronic Resource
    Electronic Resource
    The pharmacokinetics of ketoconazole after chronic administration in adults (1987)
    Springer
    European journal of clinical pharmacology 33 (1987), S. 531-534 
    Details
    ISSN: 1432-1041
    Keywords: ketoconazole ; pharmacokinetics ; antimycotic drug
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacokinetics of the anti-mycotic ketoconazole in seven patients who took it for 1–6 months at a dose of 200 mg daily. The mean elimination half-life of the drug was 3.3 h, and although the ketoconazole was given only once daily, a satisfactory clinical response was obtained in all seven individuals. Only a small fraction of the absorbed drug (mean 0.22%) was excreted unchanged in the urine, suggesting almost complete metabolism. Our results support the concept that anti-mycotic activity in the tissues continues after the plasma drug concentration has fallen below a critical level. Our results also support the concept of a change in pharmacokinetics with chronic dosing.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00544251
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  • 300
    Electronic Resource
    Electronic Resource
    Effects of josamycin on carbamazepine kinetics (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 321-323 
    Details
    ISSN: 1432-1041
    Keywords: carbamazepine ; josamycin ; drug interaction ; epileptic patients ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The steady state pharmacokinetics of oral carbamazepine in epileptic patients (n=8) was compared before and after one week of treatment with josamycin (2 g/day). There was a small but statistically significant decrease in oral clearance of total (17%) and unbound (21.5%) drug. In spite of an unchanged AUC of 10,11-epoxide carbamazepine the ratio of metabolite to parent drug AUC was significantly decreased (20.2%). The plasma protein binding of carbamazepine and its 10,11-epoxide metabolite did not vary. The results demonstrate impairment by josamycin of the apparent clearance of carbamazepine. Care should be taken in patient receiving both carbamazepine and josamycin.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00607583
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