Ethnic and genetic determinants of omeprazole disposition and effect

Objectives: To compare the pharmacokinetics and dynamics of omeprazole in white and Chinese subjects. Methods: This double-blind two-stage study, performed in the clinical research center of a university hospital, evaluated 15 healthy nonsmoking men (eight white subjects and seven Chinese extensive metabolizers of mephenytoin). Blood samples were obtained over 24 hours after the eighth omeprazole dose (40 mg/day). Omeprazole, omeprazole sulfone, and hydroxyomeprazole pharmacokinetics were calculated from the respective plasma concentration-time curves. Twelve- and 24-hour integrated plasma gastrin (AUC(gas12) and AUC(gas24)) were calculated from the respective plasma gastrin concentrations. A week before the initiation of omeprazole the activities of CYP2D6, CYP2C19, and CYP3A4 were determined by previously established methods. Results: Omeprazole concentrations were significantly lower (mean area under the plasma concentration time curve extrapolated to infinity [AUC(0-infinity)]+/-SEM; 7.53+/-1.21 versus 12.80+/-2.13 mu mol . hr . L(-1), respectively; p <0.05) and its oral clearance greater (319+/-60 versus 183+/-35 ml/min, respectively; p <0.05) in the white subjects than in the Chinese subjects. Omeprazole and omeprazole sulfone AUC(0-infinity) values were well correlated with the S/R mephenytoin ratio (r=0.82 and r=0.84, respectively; p <0.001) and with urinary 4'-hydroxymephenytoin (r=-0.58 [p <0.03] and r=-0.52 [p <0.02], respectively). Fasting gastrin, AUC(gas12) and AUC(gas24) were significantly greater in the Chinese subjects than in the white subjects (30.0+/-6.4 versus 14.4+/-1.2 pmol, respectively [p <0.02]; 661+/-114 versus 334+/-38 pmol . hr . L(-1), respectively [p <0.002]; and 1414+/-228 versus 747+/-99 pmol . hr . L(-1), respectively [p <0.004]). In addition, the S/R mephenytoin ratio and omeprazole AUC(0-infinity) correlated with the extent of omeprazole induced hypergastrinemia. Conclusion: The metabolism of omeprazole and the rise in gastrin concentration after its administration is genetically determined and ethnically dependent.