Rost K L, Roots I
Institute of Clinical Pharmacology, Universitätsklinikum Benjamin Franklin, Berlin, Germany.
Hepatology. 1996 Jun;23(6):1491-7. doi: 10.1002/hep.510230628.
Nonlinear kinetics of omeprazole and its metabolites were investigated after treatment with repeated high doses. Extensive metabolizers relating to cytochrome P450 2C19 (CYP2C19) activity received for 1 week either omeprazole at 40 mg/d (n = 14) or 60 mg/d omeprazole twice daily (n = 8). Five poor metabolizers (PMs) received 40 mg/d for 1 week. Comparison of omeprazole plasma kinetics between extensive metabolizers (EMs) and PMs after 40-mg treatment revealed a dominant role of CYP2C19 over cytochrome P450 3A CYP3A in omeprazole metabolism. Comparing the omeprazole doses of 40 mg and 60 mg in eight EMs on day 7 of treatment showed that CYP2C19-dependent plasma clearance of omeprazole and omeprazole sulfone was reduced from 19.0 to 8.4 L/h (P < .001) and from 19.8 to 9.2 L/h (P = .012), respectively. Similarly, formation half-life of 5'-hydroxyomeprazole increased from 0.58 to 1.45 hours (P = .025) with the higher dose. CYP3A-dependent metabolic routes remained unaffected. Thus, high-dose treatment with omeprazole uncovers saturation kinetics for CYP2C19 pathways in EMs, and CYP3A becomes the predominant enzyme of omeprazole elimination. Moreover, these individuals may be at risk for side effects due to high omeprazole concentrations if high-dose omeprazole treatment is combined with drugs inhibiting CYP3A activity.
在重复高剂量治疗后，对奥美拉唑及其代谢物的非线性动力学进行了研究。与细胞色素P450 2C19（CYP2C19）活性相关的广泛代谢者接受了为期1周的治疗，其中14例患者每天服用40mg奥美拉唑，8例患者每天两次服用60mg奥美拉唑。5例代谢不良者（PMs）接受了为期1周的每天40mg的治疗。比较40mg治疗后广泛代谢者（EMs）和PMs之间的奥美拉唑血浆动力学，结果显示CYP2C19在奥美拉唑代谢中比细胞色素P450 3A（CYP3A）起主导作用。在治疗第7天，比较8例EMs中40mg和60mg奥美拉唑剂量，结果显示，CYP2C19依赖性的奥美拉唑和奥美拉唑砜的血浆清除率分别从19.0降至8.4L/h（P<.001）和从19.8降至9.2L/h（P=.012）。同样，较高剂量时，5'-羟基奥美拉唑的形成半衰期从0.58小时增加至1.45小时（P=.025）。CYP3A依赖性代谢途径未受影响。因此，高剂量奥美拉唑治疗揭示了EMs中CYP2C19途径的饱和动力学，并且CYP3A成为奥美拉唑消除的主要酶。此外，如果高剂量奥美拉唑治疗与抑制CYP3A活性的药物联合使用，这些个体可能因奥美拉唑浓度过高而有发生副作用的风险。
