Kosuge K, Jun Y, Watanabe H, Kimura M, Nishimoto M, Ishizaki T, Ohashi K
Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Drug Metab Dispos. 2001 Oct;29(10):1284-9.
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 compared with 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.
地西泮在肝脏中由CYP2C19和CYP3A4代谢。CYP2C19表现出与代谢缓慢者（PM）和代谢广泛者（EM）表型相关的基因多态性。本研究的目的是评估CYP3A4抑制剂地尔硫䓬对与CYP2C19基因型状态相关的地西泮药代动力学和药效学的影响。13名健康志愿者（8名EM和5名PM）以双盲、随机、交叉方式在口服2mg地西泮前3天和后7天口服安慰剂或地尔硫䓬（200mg）。评估了有无地尔硫䓬时地西泮的药代动力学和药效学。在安慰剂阶段，PM组中地西泮和N-去甲基地西泮的血浆浓度及血浆浓度-时间曲线下面积（AUC）显著高于EM组。地尔硫䓬显著增加了PM组和EM组地西泮的AUC并延长了消除半衰期（t1/2）。然而，这些药代动力学变化在两个试验阶段的药效学上未引起显著差异。地尔硫䓬影响CYP2C19的PM组和EM组中地西泮的药代动力学。像地尔硫䓬这样的伴随底物药物对CYP3A4的抑制可能导致与地西泮的药代动力学相互作用，而与CYP2C19基因型状态无关，但我们的研究尚未证实这种相互作用是否会反映地西泮的药效学变化。
