title: Regioselectivity and stereoselectivity in the metabolism of HMG-CoA reductase inhibitors.
abstract: Biotransformation of three analogs of simvastatin, L-672,201, L-157,012 and L-672,220, by rat liver microsomes has been examined. These compounds differ from each other at the 6' position of the hexahydronaphthalene system. When 6'-substituents were in the alpha configuration, rat liver microsomes catalysed biotransformation primarily at the 6' position. Hydroxylation was stereoselective giving 6' beta-hydroxy derivatives as major metabolites. In contrast, when the 6'-substituent had a beta-configuration, metabolism at this site was blocked. Rates of metabolism (nmols/mg protein/min) also indicated that 6' beta-derivatives were poorer substrates than their 6' alpha-counterparts. The results indicate that cytochrome P-450 exhibits a high degree of regio- and stereoselectivity in the metabolism of HMG-CoA reductase inhibitors.
authors.affiliation: Department of Drug Metabolism, Merck Sharp and Dohme Research Laboratories, West Point, PA 19486.
authors.forename: K P
authors.initials: KP
authors.lastname: Vyas
authors.forename: P H
authors.initials: PH
authors.lastname: Kari
authors.forename: S M
authors.initials: SM
authors.lastname: Pitzenberger
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000378:metabolism*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D006900:Hydroxylation; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D019821:Simvastatin; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship
chemical_list: D000924:Anticholesteremic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin; D019821:Simvastatin; D010634:Phenobarbital