Vol. 29, Issue 10, 1284-1289, October 2001

Effects of CYP3A4 Inhibition by Diltiazem on Pharmacokinetics and Dynamics of Diazepam in Relation to CYP2C19 Genotype Status

Kazuhiro Kosuge, Yang Jun, Hiroshi Watanabe, Masahiko Kimura, Masahiko Nishimoto, Takashi Ishizaki, and Kyoichi Ohashi

Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, Japan (K.K., Y.J., H.W., M.K., M.N., K.O.); and Department of Pharmacology and Therapeutics, Graduate School of Clinical Pharmacy, Kumamoto University, Kumamoto, Japan (T.I.)

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.