REGIOSELECTIVITY AND STEREOSELECTIVITY IN THE METABOLISM OF HMG-COA REDUCTASE INHIBITORS

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 α configuration, rat liver microsomes catalysed biotransformation primarily at the 6′ position. Hydroxylation was stereoselective giving 6′ β-hydroxy derivatives as major metabolites. In contrast, when the 6′-substituent had a β-configuration, metabolism at this site was blocked. Rates of metabolism (nmols/mg protein/min) also indicated that 6′ β-derivatives were poorer substrates than their 6′ α-counterparts. The results indicate that cytochrome P-450 exhibits a high degree of regio- and stereoselectivity in the metabolism of HMG-CoA reductase inhibitors. © 1990.