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 μM, 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.
Footnotes
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Send reprint requests to: Dr. Leslie Z. Benet, Department of Biopharmaceutical Sciences, School of Pharmacy, University of California, 513 Parnassus Avenue, San Francisco, CA 94143-0446.
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↵1 Present address: Institut National de la Santé et de la Recherche Médicale, U-128, Route de Mende–B.P. 5051 (CNRS), 34033 Montpellier, France.
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This study was supported in part by the National Institutes of Health GM26691 and was presented at the 10th Annual Meeting of the American Association of Pharmaceutical Scientists, Seattle, WA, 1996. G.R.J. was a fellow of the American Foundation for Pharmaceutical Education–Johnson & Johnson when this work was performed.
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↵3 S. A. Wrighton, personal communication.
- Abbreviations used are::
- CYP
- cytochrome P450
- DDC
- diethyldithiocarbamic acid
- TAO
- triacetyloleandomycin
- HL
- human liver
- IC50
- 50% inhibitory concentration
- Received January 13, 1997.
- Accepted June 10, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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Cytochrome P4503A4-Mediated N-Demethylation of the Antiprogestins Lilopristone and Onapristone
