Antiprogestin-mediated inactivation of cytochrome P450 3A4

Pharmacology
G R Jang, L Z Benet

Abstract

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.

Citations

Aug 31, 2001·Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire·M Bani-YaghoubC C Naus
Mar 15, 2005·Clinical Pharmacokinetics·Shufeng ZhouHoward L McLeod
Jul 8, 2009·Arhiv za higijenu rada i toksikologiju·Vessela VitchevaMitka Mitcheva
May 9, 2002·Drug Metabolism Reviews·Slobodan Rendic
Jul 7, 2007·Critical Reviews in Toxicology·Yasuhiro Masubuchi, Toshiharu Horie
May 27, 2015·Cancer Chemotherapy and Pharmacology·Keyvan RezaiFrançois Lokiec
Jun 21, 2001·The Annals of Pharmacotherapy·R M DeHart, M S Morehead
Apr 30, 2005·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Heng-Keang LimKelvin Chan

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