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Titolo:
In vitro stimulation of warfarin metabolism by quinidine: Increases in theformation of 4 '- and 10-hydroxywarfarin
Autore:
Ngui, JS; Chen, Q; Shou, MG; Wang, RW; Stearns, RA; Baillie, TA; Tang, W;
Indirizzi:
Merck & Co Inc, Dept Drug Metab, Rahway, NJ 07065 USA Merck & Co Inc Rahway NJ USA 07065 Dept Drug Metab, Rahway, NJ 07065 USA Merck Res Labs, Dept Drug Metab, W Point, PA USA Merck Res Labs W Point PA USA Res Labs, Dept Drug Metab, W Point, PA USA
Titolo Testata:
DRUG METABOLISM AND DISPOSITION
fascicolo: 6, volume: 29, anno: 2001,
pagine: 877 - 886
SICI:
0090-9556(200106)29:6<877:IVSOWM>2.0.ZU;2-L
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN CYTOCHROME-P450 3A4; DRUG-INTERACTIONS; ACTIVATION; INHIBITION; COOPERATIVITY; KINETICS; BINDING; P450; ANTICOAGULANTS; HYDROXYLATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
45
Recensione:
Indirizzi per estratti:
Indirizzo: Tang, W Merck & Co Inc, Dept Drug Metab, POB 2000,RY800-B211, Rahway, NJ 07065 USA Merck & Co Inc POB 2000,RY800-B211 Rahway NJ USA 07065 J 07065 USA
Citazione:
J.S. Ngui et al., "In vitro stimulation of warfarin metabolism by quinidine: Increases in theformation of 4 '- and 10-hydroxywarfarin", DRUG META D, 29(6), 2001, pp. 877-886

Abstract

It has been demonstrated that the activity of cytochrome P450 (CYP)3A4 in certain cases is stimulated by quinidine (positive heterotropic cooperativity). We report herein that the 4'- and 10-hydroxylation of S- and R-warfarin are enhanced in human liver microsomal incubations containing quinidine. These reactions were catalyzed by CYP3A4, based on data derived from immunoinhibitory studies, with 4'-hydroxylation being preferentially associated with S-warfarin and 10-hydroxylation with R-warfarin. The 4'-hydroxylation of S-warfarin and 10-hydroxylation of R-warfarin increased with increasing quinidine concentrations and maximized at similar to3- and 5-fold the valuesof controls, respectively. Stimulatory effects of quinidine also were observed with recombinant CYP3A4, suggesting that increases in warfarin metabolism were due to quinidine-mediated enhancement of CYP3A4 activity, This positive cooperativity of CYP3A4 was characterized by a 2.5-fold increase in V-max for the 4'-hydroxylation of S-warfarin and a 5-fold increase in V-max for the 10-hydroxylation of R-warfarin, with little change in K-m values. Conversely, V-max for the 3-hydroxylation of quinidine was not influenced bythe presence of warfarin, These results are consistent with previous findings suggesting the existence of more than one binding site in CYP3A4 through which interactions may occur between substrate and effector at the activesite of the enzyme, Such interactions were subsequently illustrated by a kinetic model containing two binding domains, and a good regression fit was obtained for the experimental data, Finally, stimulation of warfarin metabolism by quinidine was investigated in suspensions of human hepatocytes, andincreases in the formation of 4'- and 10-hydroxywarfarin again were observed in the presence of quinidine, indicating that this type of drug-drug interaction occurs in intact cells.

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Documento generato il 19/01/20 alle ore 11:42:50