In vitro and in vivo biotransformation of simvastatin, an inhibitor of HMG CoA reductase.

摘要: Simvastatin (SV), an analog of lovastatin, is the lactone form 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 SVA underwent microsomal metabolism. Major in vitro metabolites were 6'-OH-SV (I) and 3"-OH-SV (III) formed allylic aliphatic hydroxylation, respectively, 6'-exomethylene-SV (IV) dehydrogenation. In rats, dogs, humans, biliary excretion major route elimination. Biliary (as both acids lactones) also included 6'-CH2OH-SV (V) 6'-COOH-SV (VI) 6'-chiral center had been inverted. High levels esterase rodent favored formation from SV. The 8a'-hexahydro-2', 6'-dimethyl-8'-(2",2"-dimethyl-1-oxobutoxy)-1'-naphthalene-pentano ic (VII) only rodents represented a species difference metabolism It proposed that VII beta-oxidation pathways fatty intermediary Several resulting oxidation (after subsequent conversion lactones to acids) are effective inhibitors reductase may contribute lowering effect Qualitatively, closely resembles lovastatin.