Metabolism and excretion studies in mouse after single and multiple oral doses of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor atorvastatin.
Atorvastatin, [(R-(R,R)]-2-(4-fluorophenyl)-beta, delta-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, beta-oxidized, and unsaturated derivatives of AT. Most metabolites had undergone beta-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 beta-oxidation pathway.
Department of Pharmacokinetics and Drug Metabolism, Parke-Davis Pharmaceutical Research Company, Ann Arbor, MI 48106, USA.
A E
AE
Black
M W
MW
Sinz
R N
RN
Hayes
T F
TF
Woolf
D000284:Administration, Oral; D000818:Animals; D000924:Anticholesteremic Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D000069059:Atorvastatin; D002250:Carbon Radioisotopes; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism; D004334:Drug Administration Schedule; D004790:Enzyme Induction; D005243:Feces / Q000737:chemistry; D006538:Heptanoic Acids / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011758:Pyrroles / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*
D000924:Anticholesteremic Agents; D002250:Carbon Radioisotopes; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D003577:Cytochrome P-450 Enzyme System; D000069059:Atorvastatin