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Published on: March 28, 2017
Metabolism of pravastatin sodium by 3 alpha-hydroxysteroid dehydrogenase
S Muramatsu1, Y Komokata, Y Tanaka
1Analytical and Metabolic Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
Abstract:
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'beta-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, 3 alpha-hydroxysteroids (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.
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