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PubMedDate not supplied

Pharmacokinetics of lisinopril (IV/PO) in healthy volunteers.

When 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 steady-state parameters when ten daily doses (q24h) of lisinopril were administered orally to healthy volunteers. The mean effective half-life for accumulation was 12.6 h. 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 maleate.

Administration, Oral↗

PubMedDate not supplied

Biotransformation of lovastatin. V. Species differences in in vivo metabolite profiles of mouse, rat, dog, and human.

Lovastatin is a prodrug lactone whose open-chain 3,5-dihydroxy acid is a potent, competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the rate-limiting enzyme in cholesterol biosynthesis. The compound undergoes extensive and complex metabolism in animals and humans, with the metabolites excreted predominantly in bile. Radiochromatograms of bile from three human subjects and of bile and liver homogenates from mouse, rat, and dog displayed obvious species differences. Biotransformation of lovastatin occurred by three distinct routes, namely hydrolysis of the lactone ring to yield the pharmacologically active dihydroxy acid, cytochrome P-450-mediated oxidation of the fused-ring system, and beta-oxidation of the dihydroxy acid side chain. The first two reactions occurred in all four species, but the last was observed in mouse and rat only. The P-450 reactions, hydroxylation and a novel dehydrogenation reaction, yielded a 6'-hydroxylated metabolite of the dihydroxy acid and a 6'-exomethylene derivative as major and minor metabolites, respectively, in the bile of rat and dog. Human bile, which contained predominantly polar metabolites, yielded these metabolites in similar proportions only after mild hydrolysis at pH 5.0. In mouse and rat an atypical beta-oxidation of the dihydroxy acid side chain occurred to give a pentanoic acid derivative that was observed in liver homogenates. This metabolite was subsequently conjugated with taurine and excreted in the bile. From these studies, cytochrome P-450 oxidation is the primary route of phase I metabolism for lovastatin in human and dog, but beta-oxidation plays a major metabolic role in rodents.

Animals↗