Martínez C, Albet C, Agúndez J A, Herrero E, Carrillo J A, Márquez M, Benítez J, Ortiz J A
Department of Pharmacology, Medical School, University of Extremadura, Badajoz, Spain.
Clin Pharmacol Ther. 1999 Apr;65(4):369-76. doi: 10.1016/S0009-9236(99)70129-3.
The isozymes CYP1A2, CYP2D6, and CYP3A4/5 are involved in the majority of all cytochrome P450-mediated drug biotransformations. In this study we investigated the inhibition profiles of CYP1A2 (substrate: caffeine) CYP2D6 (substrate: dextromethorphan), and CYP3A4/5 (substrate: dextrorphan) by cimetidine, ranitidine, and the novel H2-receptor antagonist ebrotidine in human liver microsomes. The inhibitory effect of the drugs on the enzymes activities were as follows: CYP1A2: cimetidine >> ranitidine = ebrotidine; CYP2D6: cimetidine >>> ranitidine = ebrotidine; CYP3A4/5: ebrotidine > cimetidine >>> ranitidine. The inhibition of CYP3A4/5 enzyme activity by ebrotidine was competitive. To test whether the inhibitory effect of ebrotidine in CYP3A activity was also found in vivo, we analyzed the biodisposition of midazolam in 8 healthy volunteers. Midazolam biodisposition was significantly reduced when administered together with cimetidine (P < .05), whereas no significant inhibition was observed with ebrotidine or ranitidine compared with placebo. Psychomotor performance analysis revealed no significant effect of the observed reduction on midazolam biodisposition. We concluded that patients who are receiving treatment with drugs metabolized through CYP3A may experience enhanced drug effects as a result of pharmacokinetic interaction when treated concomitantly with cimetidine. In contrast, the effect of ranitidine or ebrotidine on CYP3A activity in vivo seems to have little clinical significance.
细胞色素P450介导的药物生物转化大多涉及同工酶CYP1A2、CYP2D6和CYP3A4/5。在本研究中，我们研究了西咪替丁、雷尼替丁和新型H2受体拮抗剂依布替丁对人肝微粒体中CYP1A2（底物：咖啡因）、CYP2D6（底物：右美沙芬）和CYP3A4/5（底物：右啡烷）的抑制谱。这些药物对酶活性的抑制作用如下：CYP1A2：西咪替丁>>雷尼替丁=依布替丁；CYP2D6：西咪替丁>>>雷尼替丁=依布替丁；CYP3A4/5：依布替丁>西咪替丁>>>雷尼替丁。依布替丁对CYP3A4/5酶活性的抑制是竞争性的。为了测试依布替丁在体内对CYP3A活性是否也有抑制作用，我们分析了8名健康志愿者体内咪达唑仑生物转化情况。与西咪替丁合用时，咪达唑仑的生物转化显著降低（P<0.05），而与安慰剂相比，依布替丁或雷尼替丁未观察到显著抑制作用。精神运动性能分析显示，观察到的咪达唑仑生物转化降低没有显著影响。我们得出结论，接受经CYP3A代谢的药物治疗的患者，与西咪替丁同时治疗时，可能会因药代动力学相互作用而使药物效果增强。相比之下，雷尼替丁或依布替丁对体内CYP3A活性的影响似乎几乎没有临床意义。
