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 two major metabolites that have already been reported. The previously uncharacterized metabolite was found to be formed by at first being enzymatically dehydrogenated to 6'-keto intermediate (R-104), followed by decomposition to give the aromatized metabolite (R-195), through spontaneous deesterification with accompanying aromatization. The PS-6'β-hydroxydehydrogenase activity was localized in cytosolic fraction and required NADP, preferentially over NAD, as a cofactor. The formation of R-195 by rat liver cytosol was strongly inhibited by indomethacin, 3α-hydroxysteroids (but not 3β-isomers) and 3-ketosteroids. The results and high substrate specificity of purified PS-6'β-hydroxydehydrogenase toward 3α-hydroxysteroids suggested that the enzyme is identical to 3α-hydroxysteroid dehydrogenase.