Differences between white subjects and Chinese subjects in the in vivo inhibition of cytochrome P450s 2C19, 2D6, and 3A by omeprazole.
OBJECTIVE
To determine the effects of omeprazole on indexes of CYP2D6, CYP2C19 and 3A in vivo activity and to compare these in white subjects and Chinese subjects.


METHODS
Omeprazole, 40 mg/day, or placebo were administered in a double-blind crossover study for 3 weeks to eight healthy white and seven Chinese male extensive metabolizers of mephenytoin and debrisoquin. Debrisoquin (10 mg), dapsone (100 mg), and mephenytoin (100 mg) were given 1 week before administration, on the last day of administration, and 3 weeks after administration, and urine was collected over 8 hours. Phenotypic trait values were obtained from the urinary recoveries of the probe drugs or their metabolites.


RESULTS
In the white subjects, omeprazole significantly inhibited CYP2C19-mediated S-mephenytoin metabolism as indicated by decreases in the urinary R/S enantiomeric ratio (63% +/- 13%; p < 0.02; mean +/- SD) and the excretion of 4'-hydroxymephenytoin (39% +/- 13%; p < 0.001). Similar but smaller changes were also noted in Chinese subjects, 22% +/- 25% (p = 0.08) and 29% +/- 13% (p < 0.002), respectively. The interracial differences in the extent of inhibition of metabolism were statistically significant (p < 0.01 and p < 0.05, respectively). In contrast, the debrisoquin urinary metabolic ratio, a measure of CYP2D6, was unaffected. The excretion of hydroxylamine dapsone-a putative probe of CYP3A activity-was reduced by 40% +/- 30% (p < 0.03) in white subjects but not in Chinese subjects.


CONCLUSIONS
Omeprazole selectively inhibits the in vivo metabolism of S-mephenytoin, consistent with the predictions based on in vitro studies. The extent of interaction is greater in subjects of white European ancestry. It is to be expected that similar situations would also occur when omeprazole is coadministered with other substrates of CYP2C19.
Caraco
Y
Y
Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-6602, USA.
Wilkinson
G R
GR
Wood
A J
AJ
D000328:Adult; D000927:Anticonvulsants / Q000378:metabolism / Q000652:urine; D001189:Aryl Hydrocarbon Hydroxylases; D044466:Asian People; D002681:China / Q000208:ethnology; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003622:Dapsone / Q000652:urine; D003647:Debrisoquin / Q000652:urine; D004311:Double-Blind Method; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008617:Mephenytoin / Q000378:metabolism / Q000652:urine; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009853:Omeprazole / Q000494:pharmacology*; D044465:White People
D000927:Anticonvulsants; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D003622:Dapsone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C104464:CYP3A protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D009853:Omeprazole; D008617:Mephenytoin; D003647:Debrisoquin