Antiprogestin-mediated inactivation of cytochrome P450 3A4.
Based on previous observations of very short periods of linearity for antiprogestin metabolite formation and the presence of a common tertiary amine moiety in each compound as the principal site of their metabolism, we hypothesized that mifepristone, lilopristone and onapristone are oxidized by cytochrome P450 (CYP) 3A4 to reactive nitroso species that complex the heme of the enzyme, thereby inactivating it. Upon preincubation with human liver microsomes in the presence (but not the absence) of NADPH, mifepristone inhibited midazolam 1'-hydroxylation, a marker of CYP3A4 catalytic activity, very potently (IC50 approximately 3.5 mumol/l) and extensively (by approximately 87%). Lilopristone and onapristone also displayed NADPH and time-dependent inactivation of CYP3A4 with characteristics very similar to mifepristone. These data support antiprogestin-mediated inactivation of CYP3A4 and suggest the potential for drug-drug interactions and time-dependent nonlinearities in pharmacokinetics upon their long-term administration.
Jang
G R
GR
Department of Biopharmaceutical Sciences, School of Pharmacy, University of California at San Francisco, USA.
Benet
L Z
LZ
D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology*; D006067:Gonanes / Q000494:pharmacology*; D006727:Hormone Antagonists / Q000494:pharmacology*; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D008874:Midazolam / Q000032:analysis / Q000737:chemistry; D015735:Mifepristone / Q000494:pharmacology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D009249:NADP / Q000494:pharmacology; D013053:Spectrophotometry; D014019:Tissue Donors
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D004963:Estrenes; D006067:Gonanes; D006727:Hormone Antagonists; D015735:Mifepristone; C048260:lilopristone; D009249:NADP; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C053238:onapristone; D008874:Midazolam