Structural characterization of in vivo rat glutathione adducts and a hydroxylated metabolite of simvastatin hydroxy acid.

Simvastatin hydroxy acid (SVA), the pharmacologically active form of simvastatin (SV), is a potent inhibitor of 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A reductase and is formed on hydrolysis of the orally administered SV. In this article, we report the structural characterization of two new dihydroxy glutathione adducts and a trihydroxy derivative of SVA, all found in rat bile. Metabolite I is 5'beta,6'beta-dihydroxy-4'a(alpha)-glutathione-SVA, and metabolite II is a pentanoic acid derivative of metabolite I. The two identified GSH conjugates accounted for 16 and 9% in males and 11 and 5% in females of the total radioactivity (metabolites I and II, respectively). Metabolite III is 3',5'beta,6'beta-dihydrotriol-SVA and accounts for 2% (male) and 4% (female) of the total dose in rats. Of these three newly identified metabolites, only metabolite III was also observed in dog bile.