In vitro metabolism of simvastatin in humans [SBT]identification of metabolizing enzymes and effect of the drug on hepatic P450s. Drug Metabolism and Disposition

Simvastatin (SV) is a lactone prodrug used for the treatment of hypercholesterolemia. Upon incubation of SV with liver microso-mal preparations from human donors, four major metabolic prod-ucts were formed (3*-hydroxy SV, 6*-exomethylene SV, 3*,5*-dihy-drodiol SV, and the active hydroxy acid, SVA), together with several minor unidentified metabolites. The 3*,5*-dihydrodiol SV, a new metabolite, was inactive as an inhibitor of HMG-CoA reductase. Kinetic studies of SV metabolism in human liver microsomes sug-gested that the major NADPH-dependent metabolites (3*-hydroxy SV, 6*-exomethylene SV, and 3*,5*-dihydrodiol SV) were formed with relatively high intrinsic clearances, consistent with the exten-sive metabolism of SV observed in vivo. Based on four different in vitro approaches, namely 1) correlation analysis, 2) chemical inhi-bition, 3) immunoinhibition, and 4) metabolism by recombinant human P450, it is concluded that CYP3A is the major enzym