PT - JOURNAL ARTICLE AU - S Vickers AU - C A Duncan AU - K P Vyas AU - P H Kari AU - B Arison AU - S R Prakash AU - H G Ramjit AU - S M Pitzenberger AU - G Stokker AU - D E Duggan TI - In vitro and in vivo biotransformation of simvastatin, an inhibitor of HMG CoA reductase. DP - 1990 Jul 01 TA - Drug Metabolism and Disposition PG - 476--483 VI - 18 IP - 4 4099 - http://dmd.aspetjournals.org/content/18/4/476.short 4100 - http://dmd.aspetjournals.org/content/18/4/476.full SO - Drug Metab Dispos1990 Jul 01; 18 AB - Simvastatin (SV), an analog of lovastatin, is the lactone form of 1', 2', 6', 7', 8', 8a'-hexahydro-3,5-dihydroxy-2', 6'-dimethyl-8' (2", 2"-dimethyl-1"-oxobutoxy)-1'-naphthalene-heptanoic acid (SVA) which lowers plasma cholesterol by inhibiting 3-hydroxy-3-methylglutaryl-CoA reductase. SV but not its corresponding hydroxy acid form SVA underwent microsomal metabolism. Major in vitro metabolites were 6'-OH-SV (I) and 3"-OH-SV (III) formed by allylic and aliphatic hydroxylation, respectively, and 6'-exomethylene-SV (IV) formed by dehydrogenation. In rats, dogs, and humans, biliary excretion is the major route of elimination. Biliary metabolites (as both hydroxy acids and lactones) also included 6'-CH2OH-SV (V) and 6'-COOH-SV (VI) in both of which the 6'-chiral center had been inverted. High levels of esterase in rodent plasma favored the formation of SVA from SV. The formation of 1', 2', 6', 7', 8', 8a'-hexahydro-2', 6'-dimethyl-8'-(2",2"-dimethyl-1-oxobutoxy)-1'-naphthalene-pentano ic acid (VII) only in rodents represented a species difference in the metabolism of SV. It is proposed that VII is formed by beta-oxidation pathways of fatty acid intermediary metabolism. Several metabolites resulting from microsomal oxidation (after subsequent conversion from lactones to hydroxy acids) are effective inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase and may contribute to the cholesterol lowering effect of SV. Qualitatively, the metabolism of SV closely resembles that of lovastatin.