Y Caraco1, T Tateishi, A J Wood. 1. Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA.
Abstract
OBJECTIVES: To compare the effect of omeprazole, a substrate and inhibitor of CYP2C19, on diazepam metabolism in white and Chinese subjects. SUBJECTS AND METHODS: The study, which took place at a clinical research center in a University Hospital, was designed as a double blind, crossover, two-stage study; each stage lasted 21 days and was separated by 4 weeks. Subjects were eight white and seven Chinese men who were extensive metabolizers of debrisoquin and mephenytoin. The subjects received, in a randomized order, omeprazole, 40 mg/day, and placebo for 21 days, followed by a 10 mg oral dose of diazepam. Diazepam and desmethyldiazepam plasma concentrations were determined by HPLC during a 26-day period after diazepam administration. RESULTS: In white subjects omeprazole treatment decreased diazepam clearance by 38% +/- 4.4% and increased desmethyldiazepam area under the plasma concentration-time curve (AUC) by 42.4% +/- 7.0%. In contrast, diazepam oral clearance decreased by only 20.7% +/- 7.3% and desmethyldiazepam AUC decreased by 25.4% +/- 4.6% in the Chinese group. The decrease in diazepam clearance and the prolongation in diazepam and desmethyldiazepam elimination half-lives after administration of omeprazole were significantly greater in the white group than in the Chinese group (p < 0.03, p < 0.001, and p < 0.004, respectively). In the absence of omeprazole, diazepam oral clearance was marginally greater (mean +/- SEM) (34.4 +/- 2.8 ml/min versus 25.2 +/- 3.5 ml/min, p = 0.057, respectively) and the AUC of desmethyldiazepam was significantly lower (8794 +/- 538 micrograms/L.hr versus 16,358 +/- 2985 mg/L.hr, p = 0.04, respectively) in the white subjects compared with the Chinese subjects. CONCLUSION: The extent of the inhibitory effect of omeprazole on diazepam metabolism is dependent on ethnicity. Further studies are needed to determine the mechanism responsible for this phenomenon.
RCT Entities:
OBJECTIVES: To compare the effect of omeprazole, a substrate and inhibitor of CYP2C19, on diazepam metabolism in white and Chinese subjects. SUBJECTS AND METHODS: The study, which took place at a clinical research center in a University Hospital, was designed as a double blind, crossover, two-stage study; each stage lasted 21 days and was separated by 4 weeks. Subjects were eight white and seven Chinese men who were extensive metabolizers of debrisoquin and mephenytoin. The subjects received, in a randomized order, omeprazole, 40 mg/day, and placebo for 21 days, followed by a 10 mg oral dose of diazepam. Diazepam and desmethyldiazepam plasma concentrations were determined by HPLC during a 26-day period after diazepam administration. RESULTS: In white subjects omeprazole treatment decreased diazepam clearance by 38% +/- 4.4% and increased desmethyldiazepam area under the plasma concentration-time curve (AUC) by 42.4% +/- 7.0%. In contrast, diazepam oral clearance decreased by only 20.7% +/- 7.3% and desmethyldiazepam AUC decreased by 25.4% +/- 4.6% in the Chinese group. The decrease in diazepam clearance and the prolongation in diazepam and desmethyldiazepam elimination half-lives after administration of omeprazole were significantly greater in the white group than in the Chinese group (p < 0.03, p < 0.001, and p < 0.004, respectively). In the absence of omeprazole, diazepam oral clearance was marginally greater (mean +/- SEM) (34.4 +/- 2.8 ml/min versus 25.2 +/- 3.5 ml/min, p = 0.057, respectively) and the AUC of desmethyldiazepam was significantly lower (8794 +/- 538 micrograms/L.hr versus 16,358 +/- 2985 mg/L.hr, p = 0.04, respectively) in the white subjects compared with the Chinese subjects. CONCLUSION: The extent of the inhibitory effect of omeprazole on diazepam metabolism is dependent on ethnicity. Further studies are needed to determine the mechanism responsible for this phenomenon.
Authors: Nina Isoherranen; Justin D Lutz; Sophie P Chung; Houda Hachad; Rene H Levy; Isabelle Ragueneau-Majlessi Journal: Chem Res Toxicol Date: 2012-09-27 Impact factor: 3.739
Authors: M A van Agtmael; C A Van Der Graaf; T K Dien; R P Koopmans; C J van Boxtel Journal: Eur J Drug Metab Pharmacokinet Date: 1998 Jul-Sep Impact factor: 2.441