title: In vitro and in vivo biotransformation of simvastatin, an inhibitor of HMG CoA reductase.
abstract: 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.
authors.affiliation: Merck Sharp & Dohme Research Laboratories, West Point, PA 19486.
authors.forename: S
authors.initials: S
authors.lastname: Vickers
authors.forename: C A
authors.initials: CA
authors.lastname: Duncan
authors.forename: K P
authors.initials: KP
authors.lastname: Vyas
authors.forename: P H
authors.initials: PH
authors.lastname: Kari
authors.forename: B
authors.initials: B
authors.lastname: Arison
authors.forename: S R
authors.initials: SR
authors.lastname: Prakash
authors.forename: H G
authors.initials: HG
authors.lastname: Ramjit
authors.forename: S M
authors.initials: SM
authors.lastname: Pitzenberger
authors.forename: G
authors.initials: G
authors.lastname: Stokker
authors.forename: D E
authors.initials: DE
authors.lastname: Duggan
mesh_terms: D000368:Aged; D000818:Animals; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006937:Hypercholesterolemia / Q000097:blood; D066298:In Vitro Techniques; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D051381:Rats; D011919:Rats, Inbred Strains; D019821:Simvastatin; D013045:Species Specificity; D013056:Spectrophotometry, Ultraviolet
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin; D019821:Simvastatin