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Titolo:
Effects of CYP3A4 inhibition by diltiazem on pharmacokinetics and dynamicsof diazepam in relation to CYP2C19 genotype status
Autore:
Kosuge, K; Jun, Y; Watanabe, H; Kimura, M; Nishimoto, M; Ishizaki, T; Ohashi, K;
Indirizzi:
Hamamatsu Univ, Sch Med, Dept Clin Pharmacol & Therapeut, Hamamatsu, Shizuoka 4313192, Japan Hamamatsu Univ Hamamatsu Shizuoka Japan 4313192 , Shizuoka 4313192, Japan Kumamoto Univ, Grad Sch Clin Pharm, Dept Pharmacol & Therapeut, Kumamoto, Japan Kumamoto Univ Kumamoto Japan ept Pharmacol & Therapeut, Kumamoto, Japan
Titolo Testata:
DRUG METABOLISM AND DISPOSITION
fascicolo: 10, volume: 29, anno: 2001,
pagine: 1284 - 1289
SICI:
0090-9556(200110)29:10<1284:EOCIBD>2.0.ZU;2-3
Fonte:
ISI
Lingua:
ENG
Soggetto:
S-MEPHENYTOIN 4'-HYDROXYLATION; INTERMEDIATE COMPLEX-FORMATION; IN-VIVO INHIBITION; POOR METABOLIZERS; GENETIC-POLYMORPHISM; CHINESE SUBJECTS; N-DEMETHYLATION; OMEPRAZOLE; JAPANESE; HYDROXYLATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
40
Recensione:
Indirizzi per estratti:
Indirizzo: Kosuge, K Hamamatsu Univ, Sch Med, Dept Clin Pharmacol & Therapeut, 1-20-1Handayama, Hamamatsu, Shizuoka 4313192, Japan Hamamatsu Univ 1-20-1 Handayama Hamamatsu Shizuoka Japan 4313192
Citazione:
K. Kosuge et al., "Effects of CYP3A4 inhibition by diltiazem on pharmacokinetics and dynamicsof diazepam in relation to CYP2C19 genotype status", DRUG META D, 29(10), 2001, pp. 1284-1289

Abstract

Diazepam is metabolized by CYP2C19 and CYP3A4 in the liver. CYP2C19 shows genetic polymorphism associated with the poor metabolizer (PM) and extensive metabolizer (EM) phenotypes. The aim of this study was to assess the effect of diltiazem, a CYP3A4 inhibitor, on pharmacokinetics and dynamics of diazepam in relation to CYP2C19 genotype status. Thirteen healthy volunteers (eight EMs and five PMs) were given placebo or diltiazem (200 mg) orally for 3 days before and for 7 days after the oral 2-mg dose of diazepam in a double-blind, randomized, crossover manner. The pharmacokinetics and pharmacodynamics of diazepam were assessed with and without diltiazem. Plasma concentrations and area under the plasma concentration-time curves (AUCs) of diazepam and N-desmethyldiazepam were significantly greater in the PM comparedwith the EM group during the placebo phase. Diltiazem significantly increased AUC and prolonged elimination t(1/2) of diazepam in both the PM and EM groups. These pharmacokinetic changes, however, caused no significant difference in the pharmacodynamics between the two trial phases. Diltiazem affects the pharmacokinetics of diazepam in the PM and EM groups of CYP2C19. Inhibition of CYP3A4 by a concomitant substrate drug like diltiazem may cause a pharmacokinetic interaction with diazepam irrespective of CYP2C19 genotype status, but whether this interaction would reflect a pharmacodynamic change of diazepam remains unconfirmed by our study.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 25/01/20 alle ore 15:49:48