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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Tibolone Metabolism in Human Liver Is Catalyzed by 3/3-Hydroxysteroid Dehydrogenase Activities of the Four Isoforms of the Aldo-Keto Reductase (AKR)1C Subfamily

Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania (S.S., B.O., Y.J., S.-H.L., T.M.P.); and Research and Development Laboratories, NV Organon, Oss, The Netherlands (H.J.K.)

Tibolone [[7,17]-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one] is used to treat climacteric symptoms and prevent osteoporosis. It exerts tissue-selective effects via site-specific metabolism into 3- and 3-hydroxymetabolites and a ⁴-isomer. Recombinant human cytosolic aldo-keto reductases 1C1 and 1C2 (AKR1C1 and AKR1C2) produce 3-hydroxytibolone, and the liver-specific AKR1C4 produces predominantly 3-hydroxytibolone. These observations may account for the appearance of 3-hydroxytibolone in target tissues and 3-hydroxytibolone in the circulation. Using liver autopsy samples (which express AKR1C1-AKR1C4), tibolone was reduced via 3- and 3-hydroxysteroid dehydrogenase (HSD) activity. 3-Hydroxytibolone was exclusively formed in the cytosol and was inhibited by the AKR1C2-specific inhibitor 5-cholanic acid-3, 7-diol. The cytosolic formation of 3-hydroxytibolone was inhibited by an AKR1C4-selective inhibitor, phenolphthalein. The ratio of these stereoisomers was 4:1 in favor of 3-hydroxytibolone. In HepG2 cell cytosol and intact cells (which do not express AKR1C4), tibolone was exclusively reduced to 3-hydroxytibolone and was blocked by the AKR1C1-AKR1C3 inhibitor flufenamic acid. In primary hepatocytes (which express AKR1C1-AKR1C4), time-dependent reduction of tibolone into 3- and 3-hydroxytibolone was observed again in a 4:1 ratio. 3-HSD activity was inhibited by both 5-cholanic acid-3,7-diol and flufenamic acid, implicating a role for AKR1C2 and AKR1C1. By contrast, the formation of 3-hydroxytibolone was exclusively inhibited by phenolphthalein implicating AKR1C4 in this reaction. 3- and 3-Hydroxytibolone were rapidly metabolized into polar metabolites (>85%). The formation of minor amounts of tibolone was also observed followed by AKR1C-catalyzed epimerization. The low hepatic formation of 3-hydroxytibolone suggests that AKR1C4 is not the primary source of this metabolite and instead it maybe formed by an intestinal or enterobacterial 3-HSD.

Address correspondence to: Dr. Trevor M. Penning, Department of Pharmacology, University of Pennsylvania, 130C John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104-6084. E-mail: penning{at}pharm.med.upenn.edu

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