Caraco Y, Wilkinson G R, Wood A J
Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-6602, USA.
Clin Pharmacol Ther. 1996 Oct;60(4):396-404. doi: 10.1016/S0009-9236(96)90196-4.
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.
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.
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.
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.
确定奥美拉唑对细胞色素P450 2D6（CYP2D6）、细胞色素P450 2C19（CYP2C19）及3A体内活性指标的影响，并在白种人和中国受试者中进行比较。
在一项双盲交叉研究中，8名健康白种男性和7名中国男性美芬妥英和异喹胍的广泛代谢者接受为期3周的治疗，分别给予40mg/天的奥美拉唑或安慰剂。在给药前1周、给药最后一天及给药后3周给予异喹胍（10mg）、氨苯砜（100mg）和美芬妥英（100mg），并收集8小时尿液。通过探针药物或其代谢产物的尿回收率获得表型特征值。
在白种受试者中，奥美拉唑显著抑制CYP2C19介导的S-美芬妥英代谢，表现为尿中R/S对映体比率降低（63%±13%；p<0.02；均值±标准差）及4'-羟基美芬妥英排泄减少（39%±13%；p<0.001）。中国受试者中也观察到类似但较小的变化，分别为22%±25%（p=0.08）和29%±13%（p<0.002）。代谢抑制程度的种族差异具有统计学意义（分别为p<0.01和p<0.05）。相比之下，作为CYP2D6指标的异喹胍尿代谢比率未受影响。作为CYP3A活性假定探针的氨苯砜羟胺排泄在白种受试者中降低了40%±30%（p<0.03），而在中国受试者中未降低。
奥美拉唑选择性抑制S-美芬妥英的体内代谢，与基于体外研究的预测一致。在欧洲白种人受试者中相互作用程度更大。预计奥美拉唑与其他CYP2C19底物合用时也会出现类似情况。
