Abstract

Biotransformation of cerivastatin, a new cholesterol-lowering drug, by human liver microsomes was investigated using the¹⁴C-labeled drug. Metabolite profiles were established by HPLC and structures of metabolites were elucidated. Two metabolic pathways were equally important, demethylation of the benzylic methyl ether and hydroxylation at one methyl group of the 6-isopropyl substituent. The product of combined hydroxylation and demethylation was observed as a minor metabolite. During sample preparation the lactone forms of both primary metabolites were isolated in small amounts. Detailed structural analysis by NMR and LC-ESI-MS showed that hydroxylation occurred with high regio- and stereoselectivity. The proposed structures were confirmed by chemical synthesis of enantiomerically pure reference compounds. Microsomes from a human lymphoblastoid AHH-1 cell line, stably expressing CYP 3A4, catalyzed the demethylation reaction. Upon incubation of cerivastatin with human liver microsomes in the presence of the specific CYP 3A inhibitor TAO, both hydroxylation and demethylation were considerably reduced. This indicates that CYP 3A enzymes play a major role in cerivastatin metabolism.