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Ethnic and genetic determinants of omeprazole disposition and effect
Author(s) -
Caraco Yoseph,
Lagerstrom PerOlaf,
Wood Alastair J.J.
Publication year - 1996
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/s0009-9236(96)90131-9
Subject(s) - disposition , omeprazole , ethnic group , pharmacology , medicine , psychology , political science , social psychology , law
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‐∞ ] ± SEM; 7.53 ± 1.21 versus 12.80 ± 2.13 μmol · 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‐∞ values were well correlated with the SR 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‐∞ 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. Clinical Pharmacology & Therapeutics (1996) 60 , 157–167; doi: