摘要:

AbstractClinically, absorption and elimination of most drugs follow linear kinetics, and pharmacokinetic parameters describing absorption and elimination of a drug do not change over the therapeutic dose range. However, dose‐dependent pharmacokinetics have been reported more frequently in preclinical studies, particularly in toxicity studies, where high doses are often employed. This review highlights the major types of dose‐dependent pharmacokinetics with unique examples.Before setting out on a pivotal subchronic and chronic toxicity study of a new drug, a pilot study is often performed to establish a dose range in which a reasonable relationship between plasma AUC and dosage exists to ensure sufficient exposure of animals to the drug. Theoretical bases and possible causes of dose‐AUC disproportionality are discussed.Factors affecting the distribution and elimination of drugs and causes of dose‐dependent tissue distribution and elimination are also discussed. Often, the non‐linear kinetics complicate the design of dosage regimens and prediction of efficacy and toxicity. Thus, an understanding of the influence of dose on the pharmacokinetics is important in the evaluation of the efficacy and toxicity of

ISSN:0142-2782    

DOI:10.1002/bdd.2510150102

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractIt is likely that a proportion of people treated with the anti‐schistosomicidal drug praziquantel (PZQ) is also taking other drugs such as chloroquine (CHQ), a widely used anti‐malarial. The effect of CHQ on the pharmacokinetics and metabolism of PZQ in rats and in humans was therefore studied. CHQ decreased the bioavailability of PZQ and reduced its maximum serum concentrations to a significant extent in rats and in humans. The clearance was increased to a statistically significant extent in rats but not in humans because of the wide interindividual variation. The effect of CHQ on PZQ pharmacokinetics was unexpected since drugs that inhibit hepatic drug metabolism usually increase the bioavailability of PZQ. We found that CHQ inhibits non‐competitively the metabolism of PZQ to its major metabolite, 4‐hydroxy‐praziquantel, with aKiof 1.65 mM in rat hepatic microsomes. Maximum concentrations attained by CHQ in serum, however, are low compared to theKivalue and significant inhibition is therefore unlikelyin vivo.The explanation for CHQ's effect on the pharmacokinetics of PZQ may be due to other effects of CHQ rather than to a direct effect on drug‐metaboliz

ISSN:0142-2782    

DOI:10.1002/bdd.2510150103

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractThe pharmacokinetics of two new sustained‐release (SR) products of diltiazem, Dilapress 120 mg tablets and Dilapress 240 mg tablets, was analysed and characterized in three different studies, in comparison to the following diltiazem SR formulations: Cardizem Retard, Cardizem SR, and Cardizem CD. Dilapress 120, designated for twice‐daily dosing, was found to be bioequivalent to Cardizem SR and to Cardizem Retard with mean (±SD) relative bioavailability values of 99 ± 27% and 113 ± 38%, respectively. Dilapress 240, designed for once‐a‐day treatment, was found to have a slower absorption rate than Cardizem SR and its extent of absorption was 56 ± 19% relative to that of Cardizem SR. However, the bioavailability of Dilapress 240 relative to that of Cardizem CD was 118±46%, indicating that the bioavailability of Cardizem CD relative to that of Cardizem SR was only 54±29%. Diltiazem is partially available due to a saturable liver first‐pass effect. A high dose of Cardizem SR may partially escape this first‐pass effect and, thus, achieve a higher extent of absorption than a slower SR product. Consequently, SR products of diltiazem designed for once‐daily treatment may not reach the saturation stage in the liver first‐pass effect process that diltiazem is susceptible to. Consequently, a twice‐daily SR product of diltiazem cannot serve as a reference for extent of absorption assessments of

ISSN:0142-2782    

DOI:10.1002/bdd.2510150104

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractDuP 532, 2‐propyl‐4‐pentafluoroethyl‐1‐{[2′‐(1H‐tetrazol‐5‐yl)biphenyl‐4‐yl] methyl} imidazole‐5‐carboxylic acid, is an orally active, non‐peptide angiotensin II (AII) receptor antagonist. DuP 532 is more potent and longer acting than losartan, another AII receptor antagonist currently undergoing phase III clinical trials. The pharmacokinetics and the effect of the salt form on the bioavailability of DuP 532 were determined in rats and dogs. In rats, the absolute oral bioavailability and half‐life averaged 8·0% and 3·5 h, respectively, after the sodium bicarbonate solution and 7·6% and 3·6 h, respectively, after the methyl cellulose suspension. In dogs, the absolute oral bioavailability averaged 13.4% after the sodium bicarbonate solution and 11·9% after hard gelatin capsules containing the neat powder. The data demonstrated that there were no differences in bioavailability between the free acid and the sodium salt of DuP 532 after oral administration to rats and dogs.Thein vitrometabolism of14C‐DuP 532 was evaluated with rat, dog, and human liver microsomes. HPLC analyses with UV and radiochemical flow detection showed that recovery of DuP 532 was greater than 99%, suggesting that there was little if any metabolism by liver microsomal enzymes. Therefore, the low oral bioavailability in rats was probably due to poor absorption of DuP 532 from the GI

ISSN:0142-2782    

DOI:10.1002/bdd.2510150105

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractThe aim of this investigation was to assess the pharmacokinetics and bioavailability of ergometrine in six human male subjects after an oral dose of 0·200 mg and after an intravenous dose of 0·075 mg of ergometrine maleate. A large variation in bioavailability of between 34% and 117% in the six volunteers was observed. The lag time was also subject dependent and ranged between 0·0073 h (0.4 mm) and 0·47 h (28 min). After intravenous administration, the pharmacokinetic profile can be described by a twocompartment model. The distribution half‐lifet1/2αis 0·18 ± 0·20 h, the elimination half‐lifet1/2βis 2·0 ± 0·90 h, the total body clearance (CL) amounts to 35·9 ± 13·41 h−1and the steady‐state volume (Vss) of distribution is 73·4 ± 22·01. After oral administration, the pharmacokinetic profile can be described by a one‐compartment model. The absorption half‐lifet1/2absis 0·19 ± 0·22 h, and the elimination half‐lifet1/2β1·90 ± 0·16 h. This study with oral ergometrine shows such a large interindividual variability in bioavailability that the oral route of administration does not seem not to be the most reliable means of accurate dosing

ISSN:0142-2782    

DOI:10.1002/bdd.2510150106

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractThe pharmacokinetics of cyclosporin A (CyA) were investigated in the rat following intravenous doses of 1·7, 3·3, and 6·4 mg kg−1and oral doses of 3·1, 6·8, and 12·9 mg kg−1. The blood concentration‐time profile after intravenous administration was adequately described by a two‐compartment model when all data were simultaneously analysed using NONMEM. The disposition pharmacokinetics were linear over the dose range studied; the average total blood clearance was 0·191 g−1kg−1. The absorption process could not be adequately described by either a first‐ or a zero‐order input. Therefore, a flexible, staircase input model was used and found to be superior to the standard models. The shape of this model was biphasic, with a higher initial input rate than expected from first‐order absorption. The duration of this first phase increased with dose. The extent of absorption was also dose dependent. Bioavailability was higher at higher doses; the values were 45%, 67% and 76% for the three ascending dose levels. These results strongly indicate a saturable first‐pass effect. Since the extraction of CyA in the liver is only 6%, the marked increase in bioavailability of CyA is most likely to be the result of sat

ISSN:0142-2782    

DOI:10.1002/bdd.2510150107

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractA single dose of 8 mg of thiocolchicoside was administered to 12 healthy volunteers according to a Latin square design, either as tablets (reference), oral solution, or intramuscular injection. Serum thiocolchicoside concentrations showed an absorption phase followed by a biexponential decay with a terminal half‐life (t1/2β) of approximately 5 h, similar for the three formulations. The relative bioavailability of both oral formulations was approximately 25%, compared to the intramuscular formulation. There was a trend for the oral solution to have a slightly larger AUC andCmax, as well as a slightly shorterTmax, than the tablet formulation. However, the comparison of the two oral forms did not show statistically significant differences in the pharmacokinetic parametersCmax,Tmax, and AUC, suggesting that the Coltramyl®tablets have an adequatein vivodissolution prof

ISSN:0142-2782    

DOI:10.1002/bdd.2510150108

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

ISSN:0142-2782    

DOI:10.1002/bdd.2510150101

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY