TY - JOUR T1 - Biotransformation of lovastatin. I. Structure elucidation of in vitro and in vivo metabolites in the rat and mouse. JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 203 LP - 211 VL - 18 IS - 2 AU - K P Vyas AU - P H Kari AU - S M Pitzenberger AU - R A Halpin AU - H G Ramjit AU - B Arison AU - J S Murphy AU - W F Hoffman AU - M S Schwartz AU - E H Ulm Y1 - 1990/03/01 UR - http://dmd.aspetjournals.org/content/18/2/203.abstract N2 - Structures of in vitro microsomal and in vivo metabolites of lovastatin, a new cholesterol-lowering drug, were elucidated with the combined application of HPLC, UV, fast atom bombardment-MS, and NMR spectroscopy. Liver microsomes from rats and mice catalyzed the biotransformation of lovastatin, primarily at the 6'-position of the molecule, to form 6'-hydroxy-lovastatin and a novel 6'-exomethylene derivative. Hydroxylation at the 6'-position occurred stereoselectively, giving 6'-beta-hydroxy-lovastatin. Stereoselective hydroxylation at the 3"-position of the methylbutyryl side chain and hydrolysis of the lactone group to the corresponding hydroxy acid were the other two pathways of microsomal metabolism. 3'-Hydroxy-iso-delta 4',5'-lovastatin was isolated, but is not believed to be a direct metabolite since 6'-beta-hydroxy-lovastatin rearranges to this compound under mildly acidic conditions. The major metabolites excreted in bile of rats treated with the hydroxy acid form of the drug were identified as the 3'-hydroxy analog and a taurine conjugate of a beta-oxidation product of lovastatin. The pentanoic acid derivative of lovastatin, formed by beta-oxidation of the heptanoic acid moiety, was a major metabolite in livers of mice dosed with the hydroxy acid form of lovastatin. The microsomal metabolites, in their hydroxy acid forms, were active inhibitors of HMG-CoA reductase. The relative enzyme inhibitory activities of hydroxy acid forms of lovastatin, 6'-beta-hydroxy-, 6'-exomethylene-, and 3"-hydroxy-lovastatin were 1, 0.6, 0.5, and 0.15, respectively. ER -