TY - JOUR T1 - Metabolism of Norethisterone and Norethisterone Derivatives in Rat Uterus, Vagina, and Aorta JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 976 LP - 982 VL - 29 IS - 7 AU - M. J. Blom AU - M. Groot Wassink AU - F. van Wijk AU - A. G. H. Ederveen AU - H. J. Kloosterboer AU - C. H. J. Verhoeven AU - J. G. D. Lambert AU - H. J. Th. Goos Y1 - 2001/07/01 UR - http://dmd.aspetjournals.org/content/29/7/976.abstract N2 - The 19-nor-progestogen norethisterone is used as a progestogen component in contraceptives and in continuous- and sequential combined hormone replacement therapy (HRT) in postmenopausal women. Metabolism of norethisterone in HRT target tissues may play a role in its biological response. The aim of this study was to investigate which steroid-metabolizing enzymes are present in rat uterus, vagina, and aorta, three HRT target tissues. Next, the ability of the tissues to metabolize norethisterone was assessed. Furthermore, to investigate the effect of substituents at the 7- and 11-position, the metabolism of Org OM38 (7α-methyl-norethisterone), Org 4060 (11β-ethyl-norethisterone), and Org 34694 (7α-methyl,11-ethylidene-norethisterone) was studied. Using radiolabeled progesterone, the presence of 20α-hydroxysteroid dehydrogenase, 5α-reductase, and 3α-hydroxysteroid dehydrogenase activity could be demonstrated in uterus, vagina, and to a lesser extent in aorta. The combined action of the latter two enzyme activities resulted in 3α-OH,5α-H-norethisterone as the major metabolite of radiolabeled norethisterone in uterus (26.9%), vagina (37.1%), and aorta (1.4%). The norethisterone derivatives, however, were metabolized to a much lesser extent (1.0–7.6%). No formation of 5α-reduced forms of Org 4060, Org OM38, or Org 34694 was found, while formation of minor amounts of 3α-OH-Org 4060 and 3α-OH-Org OM38 could be demonstrated in both uterus, vagina, and aorta. These findings confirm the role of 5α-reductase as a rate-limiting step in the metabolism of norethisterone derivatives and show important inhibitory effects of substituents at the 7α- and 11-position of the steroid skeleton on 5α-reduction. The American Society for Pharmacology and Experimental Therapeutics ER -