title: Cytochrome P4503A4-mediated N-demethylation of the antiprogestins lilopristone and onapristone.
abstract: 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.
authors.affiliation: Department of Biopharmaceutical Sciences, School of Pharmacy, University of California at San Francisco, San Francisco, CA 94143-0446, USA.
authors.forename: G R
authors.initials: GR
authors.lastname: Jang
authors.forename: L Z
authors.initials: LZ
authors.lastname: Benet
mesh_terms: D000328:Adult; D002675:Child, Preschool; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004963:Estrenes / Q000378:metabolism*; D005260:Female; D006067:Gonanes / Q000378:metabolism*; D006727:Hormone Antagonists / Q000378:metabolism*; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009652:Norpregnenes / Q000494:pharmacology; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D011372:Progestins / Q000037:antagonists & inhibitors*; D014217:Troleandomycin / Q000494:pharmacology
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004963:Estrenes; D006067:Gonanes; D006727:Hormone Antagonists; D009652:Norpregnenes; D011372:Progestins; C033273:Gestodene; C048260:lilopristone; D003577:Cytochrome P-450 Enzyme System; D014217:Troleandomycin; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D010089:Oxidoreductases, N-Demethylating; C053238:onapristone