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Titolo:
ANTIPROGESTIN-MEDIATED INACTIVATION OF CYTOCHROME-P450 3A4
Autore:
JANG GR; BENET LZ;
Indirizzi:
UNIV CALIF SAN FRANCISCO,SCH PHARM,DEPT BIOPHARMACEUT SCI,513 PARNASSUS AVE SAN FRANCISCO CA 94143 UNIV CALIF SAN FRANCISCO,SCH PHARM,DEPT BIOPHARMACEUT SCI SAN FRANCISCO CA 94143
Titolo Testata:
Pharmacology
fascicolo: 3, volume: 56, anno: 1998,
pagine: 150 - 157
SICI:
0031-7012(1998)56:3<150:AIOC3>2.0.ZU;2-V
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN LIVER-MICROSOMES; ENDOMETRIAL MATURATION; DRUG-INTERACTIONS; METABOLISM; COMPLEXES; RU-486; MIFEPRISTONE; INHIBITION; TRIACETYLOLEANDOMYCIN; PHARMACOKINETICS;
Keywords:
ENZYME INACTIVATION; CYTOCHROME P450 3A4; ANTIPROGESTINS; MIFEPRISTONE; LILOPRISTONE; ONAPRISTONE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
32
Recensione:
Indirizzi per estratti:
Citazione:
G.R. Jang e L.Z. Benet, "ANTIPROGESTIN-MEDIATED INACTIVATION OF CYTOCHROME-P450 3A4", Pharmacology, 56(3), 1998, pp. 150-157

Abstract

Based on previous observations of very short periods of linearity forantiprogestin 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 onapristoneare oxidized by cytochrome P450 (CYP) 3A4 to reactive nitroso speciesthat 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, amarker of CYP3A4 catalytic activity, very potently(IC50 similar to 3.5 mu mol/l) and extensively (by similar to 87%). Lilopristone and onapristone also displayed NADPH and time-dependent inactivation of CYP3A4with characteristics ver?; 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.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 22/01/20 alle ore 21:38:27