氯吡格雷的体外相互作用研究

The Drug Interactions Study of Clopidogrel in vitro

目的：考察临床常与氯吡格雷合用的CYP2C19及羧酸酯酶1（CES1）的底物药物对氯吡格雷体外代谢的影响，以期为临床上氯吡格雷的合理使用提供科学依据。方法选择CYP2C19底物（奥美拉唑）和CES1底物（依那普利、奥司他韦、辛伐他汀、罗格列酮、氟西汀），通过体外人肝微粒体代谢试验研究其与氯吡格雷代谢相互作用，采用LC-MS/MS法测定微粒体酶孵育体系中氯吡格雷非活性和活性代谢产物的浓度。结果奥美拉唑显著抑制氯吡格雷活性代谢产物的生成（P＜0.05），辛伐他汀对活性及非活性代谢产物的生成均有不同程度的抑制作用，其他CES1底物对氯吡格雷活性和非活性代谢产物的产生无影响（P＞0.05）。结论奥美拉唑、辛伐他汀对氯吡格雷有不同程度的代谢抑制作用，临床上氯吡格雷与上述药物合用时可能需要考虑其相互作用。

Objective To investigate the effect of CYP2C19 and carboxylesterase 1 substrate that were often used in combination with clopidogrel in clinic and provide some useful information for the rational use of clopidogrel in clinic. Methods Omeprazole, CYP2C19 substrate, was chosen, enalapril, oseltamivir, simvastatin, rosiglitazone and fluoxetine, CES1 substrates were selected, the interactions between clopidogrel and these drugs were explored in vitro using human liver microsomes. The concentrations of clopidogrel inactive and active metabolite in the incubation system were determined by a LC-MS/MS method. Results Omeprazole significantly inhibited the formation of the clopidogrel active metabolite (P<0.05). Simvastatin exhibited varying degrees of inhibition towards the generation of both inactive and active metabolite of clopidogrel, other selected substrates did not affect the production of either inactive or active metabolite of clopidogrel (P>0.05). Conclusion Omeprazole and simvastatin showed different degrees of metabolic inhibition towards clopidogrel. When clopidogrel prescribed in combination with these drugs, the interactions of them should not be ignored in clinic.