INTERPHENOTYPE DIFFERENCES IN DISPOSITION AND EFFECT ON GASTRIN-LEVELS OF OMEPRAZOLE - SUITABILITY OF OMEPRAZOLE AS A PROBE FOR CYP2C19
INTERPHENOTYPE DIFFERENCES IN DISPOSITION AND EFFECT ON GASTRIN-LEVELS OF OMEPRAZOLE - SUITABILITY OF OMEPRAZOLE AS A PROBE FOR CYP2C19
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DOI：
10.1111/j.1365-2125.1995.tb04488.x
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发表时间：
1995-05-01
影响因子：
3.4
通讯作者：
BERTILSSON, L
中科院分区：
文献类型：
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作者：
CHANG, M;TYBRING, G;BERTILSSON, L
1 14名健康的瑞典白人受试者每天早晨口服20 mg奥美拉唑，持续8天。受试者包括5名S-美芬妥英弱代谢者（PM）、4名杂合子快代谢者（hetEM）和5名代谢非常快的受试者（rapidEM）。2首次给药后，rapidEM、hetEM和PM中奥美拉唑的相对平均血药浓度-时间曲线下面积（AUC）为1：3.7：20（均不同，P < 0.001）。在砜代谢物（1：3：12）的AUC（0，10 h）中观察到类似的关系。EM中的羟基奥美拉唑浓度高于PM，证实羟基（而非砜代谢物）是由S-美芬妥英羟化酶（CYP 2C 19）形成的。治疗8天后，组间差异相似。3第1次和第8次给药后，奥美拉唑/羟基奥美拉唑血药浓度比（在服药后3 h测定）与美芬妥英S/R比相关（r（s）= 0.94; P < 0.001; n = 14）提示奥美拉唑可能用于CYP 2C 19的表型。4奥美拉唑首次给药后，三组之间血浆胃泌素的AUC（0，10 h）无差异。从第1次给药到第8次给药，hetEM和PM中胃泌素的AUC（0，10）均显著增加，而rapidEM中无变化。第8次给药后，血浆中胃泌素的AUC（0，10）与奥美拉唑的AUC显著相关（r（s）= 0.79; P < 0.01; n = 13）。
1 Fourteen healthy Swedish Caucasian subjects were given 20 mg of omeprazole orally each morning for 8 days. The subjects included five poor metabolisers (PM) of S-mephenytoin, four heterozygous extensive metabolisers (hetEM) and five subjects with a very rapid metabolism (rapidEM).2 After the first dose, the relative mean areas under the plasma concentration vs time curve (AUG) of omeprazole in rapidEM, hetEM and PM were 1:3.7:20 (all different, P < 0.001). A similar relation was seen in the AUC(0,10 h) of the sulphone metabolite (1:3:12). Concentrations of hydroxyomeprazole were higher in EM than in PM confirming that the hydroxy, but not the sulphone metabolite, is formed by the S-mephenytoin hydroxylase (CYP2C19). After 8 days of treatment, the differences between groups were similar.3 After both the first and the eighth doses, the omeprazole/hydroxyomeprazole plasma concentration ratio, determined 3 h after drug intake, correlated with the mephenytoin S/R ratio (r(s) = 0.94; P < 0.001; n = 14) suggesting that omeprazole might be used to phenotype for CYP2C19.4 After the first dose of omeprazole, there was no difference in the AUC(0,10 h) of plasma gastrin between the three groups. From the first to the eighth dose, the AUC(0,10) of gastrin increased significantly in both hetEM and PM, while there was no change in the rapidEM. After the eighth dose, the AUC(0,10) of gastrin correlated significantly with the AUC of omeprazole in plasma (r(s) = 0.79; P < 0.01; n = 13).