Abstract

Atorvastatin, [(R-(R,R)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenyl-amino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (CI-981, AT), is a second generation 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor approved for clinical use as a cholesterol lowering agent. The disposition and metabolism of AT, including potential CYP450 induction, was investigated in mice administered an oral dose of [¹⁴C]AT (free acid) on study days 1 and 14. Peak plasma radioactivity concentrations occurred 1 hr postdose after both single- and multiple-dose administration and declined rapidly thereafter. Total plasma radioactivity levels in mice receiving the multiple dose were approximately 50% of levels observed after single-dose administration. Plasma metabolic profiles, which provided evidence of extensive metabolism, remained similar. Feces was the major route of AT-derived radioactivity elimination. Fecal profiles showed extensive metabolism with qualitatively similar profiles after single- and multiple-dose administration; however, quantitative differences were apparent. Metabolites identified in plasma and feces include hydroxylated, β-oxidized, and unsaturated derivatives of AT. Most metabolites had undergone β-oxidation. In mice receiving multiple 1 mg/kg doses of AT, no effect on spectral P450 concentration was found, and only a minor increase was observed at the 200 mg/kg dose level. Catalytic activities of CYP4501A, -2B, and -3A were not significantly affected; CYP4A activity decreased in a dose-dependent manner. Administration of multiple doses resulted in lower systemic plasma levels of total AT-derived radioactivity not readily explained by these studies. In mice, the majority of metabolites are formed primarily through the β-oxidation pathway.