Antiprogestin-mediated inactivation of cytochrome P450 3A4.

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Jang GR, Benet LZ

Antiprogestin-mediated inactivation of cytochrome P450 3A4.

Pharmacology. 1998 Mar;56(3):150-7. doi: 10.1159/000028193.

PubMed ID

9532615 [ View in PubMed

]

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.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Mifepristone	Cytochrome P450 3A4	Protein	Humans	Unknown	Substrate Inhibitor Inducer	Details