Interethnic difference in omeprazole's inhibition of diazepam metabolism.
OBJECTIVE
To compare the effect of omeprazole, a substrate and inhibitor of CYP2C19, on diazepam metabolism in white and Chinese subjects.


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.


CONCLUSIONS
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.
Caraco
Y
Y
Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA.
Tateishi
T
T
Wood
A J
AJ
D000328:Adult; D044466:Asian People; D002681:China / Q000208:ethnology; D018592:Cross-Over Studies; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003647:Debrisoquin / Q000378:metabolism; D003975:Diazepam / Q000009:adverse effects / Q000378:metabolism* / Q000493:pharmacokinetics; D004311:Double-Blind Method; D004347:Drug Interactions; D005006:Ethnicity; D006801:Humans; D008297:Male; D008617:Mephenytoin / Q000378:metabolism; D003708:Nordazepam / Q000378:metabolism / Q000493:pharmacokinetics; D009853:Omeprazole / Q000009:adverse effects / Q000494:pharmacology*; D013714:Tennessee; D044465:White People
D065607:Cytochrome P-450 Enzyme Inhibitors; D003708:Nordazepam; D003577:Cytochrome P-450 Enzyme System; D009853:Omeprazole; D003975:Diazepam; D008617:Mephenytoin; D003647:Debrisoquin