二氢吡啶类钙通道阻滞药对人肝微粒体中氯吡格雷代谢的抑制作用

Inhibitory Effects of Dihydropyridines on the Metabolism of Clopidogrel in Human Liver Microsomes

目的:研究二氢吡啶类(DHPs)钙通道阻滞药硝苯地平、氨氯地平、非洛地平对人肝微粒体中氯吡格雷代谢的影响,为临床合理用药提供参考。方法:采用人肝微粒体体外代谢模型,将0.1、1、5、10、25、50、100、200μmol/L的硝苯地平、氨氯地平、非洛地平分别与氯吡格雷(20μmol/L)在人肝微粒体中进行共孵育,孵育15 min后加入5倍体积的含内标氯雷他定的冰乙腈溶液(内标终质量浓度为500 ng/ml)终止反应。沉淀蛋白后取上清液,采用超高效液相色谱-质谱(UPLC-MS)法检测氯吡格雷的浓度,以不加DHPs药物为阴性对照计算各DHPs药物作用下氯吡格雷的代谢抑制率。结果:硝苯地平、氨氯地平、非洛地平对人肝微粒体中氯吡格雷的代谢均有一定程度的抑制作用,但200μmol/L浓度时代谢抑制率仍不及50%,提示半数抑制浓度均大于200μmol/L。结论:DHPs药物能抑制人肝微粒体中氯吡格雷的代谢,但抑制作用不强。提示DHPs药物不与氯吡格雷发生相互作用,不会影响两者临床联合使用。

OBJECTIVE：To research the effects of dihydropyridines（DHPs）including nifedipine,amlodipine and felodipine on the metabolism of clopidogrel by human liver microsomes and provide reference for rational use of drug. METHODS：in vitro human liver microsome metabolism models were used. The nifedipine,amlodipine and felodipine with concentrations of 0.1,1,5,10,25,50,100 and 200 μmol/L were respectively co-incubated with clopidogrel（20 μmol/L）in human liver microsomes. After15 min co-incubation,ice acetonitrile solution of 5 times volume containing internal standard loratadine（final internal standard mass concentration was 500 ng/ml）was added to terminate the reaction. After protein precipitation,the concentration of clopidogrel was detected in the supernatant by ultra performance liquid chromatography-tandem mass（UPLC-MS）method. The metabolic inhibition rates of clopidogrel with DHPs drug were calculated on the basis of the negative control without DHPs drug. RESULTS：Nifedipine,amlodipine and felodipine had an inhibitory effect to some extent on the metabolism of clopidogrel in human liver microsomes. However,the metabolic inhibition rate was less than 50% when the drugs with the concentration of 200 μmol/L,which showed that their median inhibitory concentrations were more than 200 μmol/L. CONCLUSIONS：DHPs drug can inhibit the metabolism of clopidogrel in human liver microsomes,but the inhibition is not strong,which suggests that DHPs and clopidogrel will not interact with each other and clinical joint use of the both will not be affected.