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Titolo:
Multisite kinetic models for CYP3A4: Simultaneous activation and inhibition of diazepam and testosterone metabolism
Autore:
Kenworthy, KE; Clarke, SE; Andrews, J; Houston, JB;
Indirizzi:
Univ Manchester, Sch Pharm & Pharmaceut Sci, Manchester M13 9PL, Lancs, England Univ Manchester Manchester Lancs England M13 9PL M13 9PL, Lancs, England GlaxoSmithKline, Dept Mech & Extrapolat Technol, Welwyn Garden City, Herts, England GlaxoSmithKline Welwyn Garden City Herts England en City, Herts, England
Titolo Testata:
DRUG METABOLISM AND DISPOSITION
fascicolo: 12, volume: 29, anno: 2001,
pagine: 1644 - 1651
SICI:
0090-9556(200112)29:12<1644:MKMFCS>2.0.ZU;2-U
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN CYTOCHROME-P450 3A4; HUMAN LIVER-MICROSOMES; IN-VITRO; ALPHA-NAPHTHOFLAVONE; DRUG-INTERACTIONS; P450 REDUCTASE; BINDING SITES; ACTIVE-SITE; STIMULATION; COOPERATIVITY;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
28
Recensione:
Indirizzi per estratti:
Indirizzo: Houston, JB Univ Manchester, Sch Pharm & Pharmaceut Sci, Manchester M13 9PL, Lancs, England Univ Manchester Manchester Lancs England M13 9PL ncs, England
Citazione:
K.E. Kenworthy et al., "Multisite kinetic models for CYP3A4: Simultaneous activation and inhibition of diazepam and testosterone metabolism", DRUG META D, 29(12), 2001, pp. 1644-1651

Abstract

Some substrates of cytochrome P450 (CYP) 3A4, the most abundant CYP in thehuman liver responsible for the metabolism of many structurally diverse therapeutic agents, do not obey classical Michaelis-Menten kinetics and demonstrate homotropic and/or heterotropic cooperativity. The unusual kinetics and differential effects observed between substrates of this enzyme confoundthe prediction of drug clearance and drug-drug interactions from in vitro data. We have investigated the hypothesis that CYP3A4 may bind multiple molecules simultaneously using diazepam (DZ) and testosterone (TS). Both substrates showed sigmoidal kinetics in B-lymphoblastoid microsomes containing arecombinant human CYP3A4 and reductase. When analyzed in combination, TS activated the formation of 3-hydroxydiazepam (3HDZ) and N-desmethyldiazepam (NDZ) (maximal activation 374 and 205%, respectively). For 3HDZ, V-max values remained constant with increasing TS, whereas the S50 and Hill values decreased, tending to make the data less sigmoidal. Similar trends were observed for the NDZ pathway. DZ inhibited the formation 6 beta -hydroxytestosterone (maximal inhibition, 45% of control), causing a decrease in V-max but no significant change to the S50 and Hill values, suggesting that DZ may inhibit via a separate effector site. Multisite rate equation models have been derived to explore the analysis of such complex kinetic data and to allowaccurate determination of the kinetic parameters for activation and inhibition. The data and models presented are consistent with proposals that CYP3A4 can bind and metabolize multiple substrate molecules simultaneously; they also provide a generic solution for the interpretation of the complex kinetic data derived from CYP3A4 substrates.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 22/01/20 alle ore 12:55:43