摘要:

AbstractMuch of the literature on research design in clinical pharmacology and pharmacokinetics emphasizes statistical concerns, thus suggesting that a primary ingredient of a valid research design is an appropriate plan for statistical analysis of data. However, statistical validity is only one of several ways to evaluate an experimental study. The present paper reviews the underlying logic and sources of invalidity of experimental drug research suggesting influences and factors which may deceive or lure an experimenter into erroneous conclusions.

ISSN:0142-2782    

DOI:10.1002/bdd.2510100402

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

ISSN:0142-2782    

DOI:10.1002/bdd.2510100403

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

AbstractThe pharmacokinetics of the new angiotensin converting enzyme (ACE) inhibitor benazepril·Ȟl were evaluated in healthy male volunteers. The single dose kinetics were established from data of 62 subjects receiving an oral 10mg dose of the drug. The steady state kinetics were investigated in 15 subjects after once‐daily oral doses of 5, 10 or 20 mg. The compound is a prodrug which, on absorption, is hydrolysed to the pharmacologically active metabolite benazeprilat. Thus, plasma concentrations and urinary excretion of parent compound and active metabolite were determined. Benazepril·Ȟl was rapidly absorbed (tmax□ 0·5 h) and rapidly eliminated from plasma (t1/2□ 0·6 h). Only trace amounts were excreted unchanged in urine. The drug was rapidly metabolized to benazeprilat (tmax□ 1·5 h). The elimination of the metabolite from plasma was biphasic. About 80 per cent of benazeprilat formed was eliminated within 24 h (t1/2□ 2·7 h), whereas the terminal phase (t1/2= 22·3 h) controlled a minor amount of elimination. About 17 per cent of dose was excreted in the 24‐h urine as benazeprilat. The drug disposition did not change during repeated oral dosing and only small accumulation of the metabolite occurred. The accumulation ratio was 1·20 for AUC and 1·24 for urinary excretion. The effective half‐life for accumulation was estimated at about 10–11 h. The comparison with other ACE inhibitors showed similarities but also marked differences with respect to the d

ISSN:0142-2782    

DOI:10.1002/bdd.2510100404

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

AbstractDiflunisal, a lipophilic salicylate, is absorbed more slowly in healthy volunteers than aspirin. In this paper we report on attempts to influence diflunisal absorption by buffering the gastric milieu. Sodium bicarbonate given together and 30 min after diflunisal tablets significantly (p8 per cent). Other pharmacokinetic parameters, including terminal half‐life and renal elimination of the compound, were not considerably influenced. These findings indicate that the absorption of diflunisal was enhanced by increased gastric pH, presumably a result of an increased solubility of diflunisal in the stomach together with faster transport into the small intestine.In one volunteer, after intravenous administration diflunisal plasma concentrations declined in a triphasic manner with a terminal half‐life of 12·8 h. The volume of distribution was approximately 10 per cent of body weight. Based on the ratio of AUC after equivalent i.v. and oral diflunisal doses, the absolute bioavailability was 89·5

ISSN:0142-2782    

DOI:10.1002/bdd.2510100405

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

AbstractThe pharmacokinetics of acetaminophen was examined in rats after administration of a single dose of 200 mg kg−1by the intra‐arterial, intravenous, portal vein, and oral routes. Levels of acetaminophen and its two major metabolites, acetaminophen‐glucuronide and acetaminophen‐sulfate, were quantitated in plasma at various time points for about 5 h after drug administration. The relative contribution of the gastrointestinal tract, liver, and lung to the oral extraction ratio (first‐pass effect after oral absorption) was determined. A mean oral extraction ratio of 0·49 was obtained. The mean relative extraction ratio of the gastrointestinal tract, liver, and lung were 0·52, 0·07, and 0, respectively, indicating a major contribution due to the gastrointestinal tract. This is in contrast to earlier studies which have indicated negligible contribution by the gastrointestinal tract to the oral first‐pass effect when lower doses were utilized. These results suggest that the relative contribution of the gastrointestinal tract and liver to the oral first‐pass effect of acetaminophen may b

ISSN:0142-2782    

DOI:10.1002/bdd.2510100406

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

AbstractWhen three intravenous doses of lisinopril were administered to healthy volunteers, area under the curve (to infinity) vs dose was linear with a positive intercept. Subtracting area under the extrapolated terminal phase of the serum profile from zero to infinity retained the linear relationship, but shifted the regression line to a zero intercept. It is postulated that the terminal phase reflects binding of drug to angiotensin‐converting enzyme (ACE). The half‐life for the terminal phase (approximately 40 h) was not predictive of steadystate parameters when ten daily doses (q24h) of lisinopril were administered orally to healthy volunteers. The mean effective half‐life for accumulation was 12·6h. The mean accumulation ratio was 1·38. Steady state was attained after the second daily dose. The observations in these studies with lisinopril are similar to those reported for enalaprilat, the active metabolite of the ACE inhibitor, enalapril

ISSN:0142-2782    

DOI:10.1002/bdd.2510100407

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

AbstractArbaprostil is an orally active prostaglandin E2analogue. It has been developed as a drug to treat ulcers induced by non‐steroidal anti‐inflammatory drugs. In this study, pharmacokinetic interactions between arbaprostil and aspirin were examined in humans after chronic doses of both drugs. Subjects received either arbaprostil (50 μg), asprin (975 mg) or arbaprostil (50 μg) and aspirin (975 mg) four times a day for 6 days and one dose on 7th day. Blood and urine samples were collected after the last dose for 6 h. Pharmacokinetic parameters of arbaprostil, aspirin, and Salicylate were determined. Coadministration of arbaprostil significantly lowered the area under curve (5·09 ± 0·32 μg hml−1vs 5·78 ± 0·29 μg hml−1, mean ± SE,p<0·05) and time (0·45 ± 0·07 h vs 0·70 ± 0·12 h,p<0·05) to reach maximal plasma concentration of aspirin (acetylsalicylate). The pharmacokinetics of salicylate were not changed by arbaprostil, nor were the pharmacokinetics of arbaprostil affected by aspirin. Coadministration of these two drugs did not appear to potentiate the side‐effects of either drug. The results suggest that arbaprostil and aspirin may be administered together without clinically significant changes in pharmacokine

ISSN:0142-2782    

DOI:10.1002/bdd.2510100408

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

AbstractThe pharmacokinetic interaction between diltiazem and amiodarone was investigated in dogs. In the presence of amiodarone, diltiazem's AUC values were significantly increased and its total body clearance and volume of distribution at steady‐state significantly decreased. This study indicates that cardiac patients on combined diltiazem‐amiodarone therapy may indeed be in a high risk situation in regards to the unexpectedly high blood levels of diltiazem induced: with the ultimate introduction of such side‐effects as (1) the lowering of blood pressure, (2) A/V block, and (3) sinus node depression. Such cases would require immediate dosage adjustment.Assuming that the data obtained in this study can be extrapolated to humans, a patient's physiological parameters should be monitored at periodic intervals and, more importantly, the patient should report the first sign of any untoward e

ISSN:0142-2782    

DOI:10.1002/bdd.2510100409

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

ISSN:0142-2782    

DOI:10.1002/bdd.2510100401

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY