gestodene and onapristone

The metabolism of two newer antiprogestational agents, lilopristone and onapristone, was investigated using human liver microsomes, and evidence was obtained supporting a principal role of cytochrome P450 (CYP) 3A4 in their N-demethylations. Kinetic studies with microsomes from three organ donors indicated lack of biphasic kinetics at substrate concentrations up to 200 microM, consistent with a single enzyme mediating the oxidations. Selective chemical inhibitors of CYP1A2 (furafylline), CYP2C9 (sulfaphenazole), CYP2D6 (quinidine), and CYP2A6/2E1 (diethyldithiocarbamic acid) did not affect initial rates of metabolism of either steroid. Gestodene and triacetyloleandomycin (selective for CYP3A enzymes) inhibited the demethylations of both antiprogestins by up to 77%. Rabbit polyclonal antibodies to CYP3A4 decreased initial rates of N-demethylation of the antihormones by up to 82%, whereas antibodies to CYP2C9 were not inhibitory. Collectively, these data thus suggest potential drug-drug interactions of these promising new therapeutic agents with concomitantly administered CYP3A4 substrates.

Topics: Adult; Child, Preschool; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Estrenes; Female; Gonanes; Hormone Antagonists; Humans; Male; Microsomes, Liver; Middle Aged; Mixed Function Oxygenases; Norpregnenes; Oxidoreductases, N-Demethylating; Progestins; Troleandomycin

Ability of progesterone, gestodene, promegestone and cyproterone acetate (CPA) to reverse antigestagenic action of onapristone in adult female guinea pigs was investigated. Onapristone (10 mg/kg, s.c.) administered on post-conception days 8-11 caused resorption of implantations and vaginal bleeding in all animals. Simultaneous administration of progesterone, gestodene or promegestone on days 7-13 successfully reversed antigestagenic action of this antiprogestin, since most animals supplemented with these progestagens had viable implantations at autopsy on day 14. CPA was, however, ineffective and animals supplemented with it had only resorbed implantations and blood in uterus and vagina like that in onapristone per se treated animals. High plasma progesterone and low PGFM concentration were generally observed in all pregnant animals bearing viable implantations. PGFM (13, 14-dihydro-15-keto PGF2 alpha) was significantly elevated by day 14 in onapristone-treated (Group II) and CPA-supplemented (Group X) animals. No discernible effect on pregnancy or post-implantation embryonic development was observed in animals treated per se with these progestagens.

Topics: Animals; Corpus Luteum; Embryo Implantation; Embryonic and Fetal Development; Female; Fetal Resorption; Gestational Age; Gonanes; Guinea Pigs; Hormone Antagonists; Norpregnenes; Pregnancy; Progesterone; Progesterone Congeners; Progestins; Promegestone; Uterine Hemorrhage