METABOLISM OF PRAVASTATIN SODIUM BY 3-ALPHA-HYDROXYSTEROID DEHYDROGENASE

When incubated with isolated rat hepatocytes, pravastatin sodium (PS) yielded a small amount of a metabolite in addition to tao major metabo lites that have already been reported. The previously uncharacterized metabolite was found to be formed by at first being enzymatically dehy drogenated to 6'-keto intermediate (R-104), followed by decomposition to give the aromatized metabolite (R-195), through spontaneous deester ification with accompanying aromatization. The PS-6'beta-hydroxydehydr ogenase activity was localized in cytosolic fraction and required NADP , preferentially over NAD, as a cofactor. The formation of R-195 by ra t liver cytosol was strongly inhibited by indomethacin, 3 alpha-hydrox ysteroids (but not 3 beta-isomers) and 3-ketosteroids. The results and high substrate specificity of purified PS-6'beta-hydroxydehydrogenase toward 3 alpha-hydroxysteroids suggested that the enzyme is identical to 3 alpha-hydroxysteroid dehydrogenase.