METABOLISM AND EXCRETION STUDIES IN MOUSE AFTER SINGLE AND MULTIPLE ORAL DOSES OF THE 3-HYDROXY-3-METHYLGLUTARYL-COA REDUCTASE INHIBITOR ATORVASTATIN

Citation
Ae. Black et al., METABOLISM AND EXCRETION STUDIES IN MOUSE AFTER SINGLE AND MULTIPLE ORAL DOSES OF THE 3-HYDROXY-3-METHYLGLUTARYL-COA REDUCTASE INHIBITOR ATORVASTATIN, Drug metabolism and disposition, 26(8), 1998, pp. 755-763
Citations number
20
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Pharmacy
ISSN journal
0090-9556
Volume
26
Issue
8
Year of publication
1998
Pages
755 - 763
Database
ISI
SICI code
0090-9556(1998)26:8<755:MAESIM>2.0.ZU;2-V
Abstract
Atorvastatin, -4-[(phenyl-amino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (CI-981, AT), is a second generation 3-hydroxy-3-methylgl utaryl-CoA reductase inhibitor approved for clinical use as a choleste rol lowering agent, The disposition and metabolism of AT, including po tential CYP450 induction, was investigated in mice administered an ora l dose of [C-14]AT (free acid) on study days 1 and 14, Peak plasma rad ioactivity concentrations occurred 1 hr postdose after both single- an d multiple-dose administration and declined rapidly thereafter. Total plasma radioactivity levels in mice receiving the multiple dose were a pproximately 50% of levels observed after single-dose administration, Plasma metabolic profiles, which provided evidence of extensive metabo lism, remained similar. Feces was the major route of AT-derived radioa ctivity elimination. Fecal profiles showed extensive metabolism with q ualitatively similar profiles after single- and multiple-dose administ ration; however, quantitative differences were apparent. Metabolites i dentified in plasma and feces include hydroxylated, beta-oxidized, and unsaturated derivatives of AT, Most metabolites had undergone beta-ox idation, In mice receiving multiple 1 mg/kg doses of AT, no effect on spectral P450 concentration was found, and only a minor increase was o bserved at the 200 mg/kg dose level. Catalytic activities of CYP4501A, -2B, and -3A were not significantly affected; CYP4A activity decrease d in a dose-dependent manner, Administration of multiple doses resulte d in lower systemic plasma levels of total AT-derived radioactivity no t readily explained by these studies, In mice, the majority of metabol ites are formed primarily through the beta-oxidation pathway.