title: Biotransformation of lovastatin. II. In vitro metabolism by rat and mouse liver microsomes and involvement of cytochrome P-450 in dehydrogenation of lovastatin.
abstract: Metabolism of lovastatin, a new cholesterol-lowering drug, by liver microsomes from rats and mice was investigated. Liver microsomes from rats catalyzed biotransformation of lovastatin at a rate of 3 nmol/mg of protein/min, whereas the rate of metabolism was 37% higher with liver microsomes from mice. The profiles of metabolites were similar, but the relative abundance of individual metabolites was species dependent. Hydroxylation at the 6'-position was the principal pathway of lovastatin biotransformation, whereas hydroxylation at the 3"-position of the side chain was a minor pathway. In both species the 6'-beta-hydroxy-lovastatin accounted for half of the total metabolism. Liver microsomes from rats produced 2- to 4-fold higher amounts of the other three metabolites, namely, 6'-exomethylene-, 3"-hydroxy-, and the hydroxy acid form, than mouse liver microsomes. The conversion of lovastatin to the novel 6'-exomethylene metabolite was catalyzed by cytochrome P-450 since it required microsomes and NADPH and was inhibited by SKF-525A, metyrapone, and 2,4,-dichloro-6-phenylphenoxyethylamine (DPEA). Furthermore, neither 6'-beta-hydroxy-lovastatin nor the 6'-hydroxymethyl analogs could be demonstrated to be intermediates in the formation of the 6'-exomethylene metabolite. The hydroxy acid form of lovastatin was not a substrate for liver microsomes from either species.
authors.affiliation: Department of Drug Metabolism, Merck Sharp & 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 R
authors.initials: SR
authors.lastname: Prakash
authors.forename: D E
authors.initials: DE
authors.lastname: Duggan
mesh_terms: D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D066298:In Vitro Techniques; D008148:Lovastatin / Q000378:metabolism*; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D011078:Polychlorinated Biphenyls / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D013045:Species Specificity; D013056:Spectrophotometry, Ultraviolet
chemical_list: C000939:2,4-dichloro-6-phenylphenoxyethylamine; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; D008148:Lovastatin; D011335:Proadifen; D011078:Polychlorinated Biphenyls; D008797:Metyrapone