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
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.