Tornio A, Filppula A M, Kailari O, Neuvonen M, Nyrönen T H, Tapaninen T, Neuvonen P J, Niemi M, Backman J T
1] Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland [2] HUSLAB, Helsinki University Central Hospital, Helsinki, Finland.
Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.
Clin Pharmacol Ther. 2014 Oct;96(4):498-507. doi: 10.1038/clpt.2014.141. Epub 2014 Jun 27.
Cerivastatin and repaglinide are substrates of cytochrome P450 (CYP)2C8, CYP3A4, and organic anion-transporting polypeptide (OATP)1B1. A recent study revealed an increased risk of rhabdomyolysis in patients using cerivastatin with clopidogrel, warranting further studies on clopidogrel interactions. In healthy volunteers, repaglinide area under the concentration-time curve (AUC(0-∞)) was increased 5.1-fold by a 300-mg loading dose of clopidogrel and 3.9-fold by continued administration of 75 mg clopidogrel daily. In vitro, we identified clopidogrel acyl-β-D-glucuronide as a potent time-dependent inhibitor of CYP2C8. A physiologically based pharmacokinetic model indicated that inactivation of CYP2C8 by clopidogrel acyl-β-D-glucuronide leads to uninterrupted 60-85% inhibition of CYP2C8 during daily clopidogrel treatment. Computational modeling resulted in docking of clopidogrel acyl-β-D-glucuronide at the CYP2C8 active site with its thiophene moiety close to heme. The results indicate that clopidogrel is a strong CYP2C8 inhibitor via its acyl-β-D-glucuronide and imply that glucuronide metabolites should be considered potential inhibitors of CYP enzymes.
西立伐他汀和瑞格列奈是细胞色素P450（CYP）2C8、CYP3A4以及有机阴离子转运多肽（OATP）1B1的底物。最近一项研究显示，使用西立伐他汀与氯吡格雷的患者发生横纹肌溶解的风险增加，这使得有必要对氯吡格雷的相互作用进行进一步研究。在健康志愿者中，氯吡格雷300mg负荷剂量使瑞格列奈的浓度-时间曲线下面积（AUC(0-∞)）增加5.1倍，每日持续服用75mg氯吡格雷则使其增加3.9倍。在体外实验中，我们确定氯吡格雷酰基-β-D-葡萄糖醛酸为CYP2C8的一种强效时间依赖性抑制剂。一个基于生理学的药代动力学模型表明，氯吡格雷酰基-β-D-葡萄糖醛酸使CYP2C8失活，导致在每日氯吡格雷治疗期间CYP2C8受到60%-85%的持续抑制。计算模型结果显示氯吡格雷酰基-β-D-葡萄糖醛酸在CYP2C8活性位点对接，其噻吩部分靠近血红素。结果表明，氯吡格雷通过其酰基-β-D-葡萄糖醛酸是一种强效的CYP2C8抑制剂，这意味着葡萄糖醛酸代谢物应被视为CYP酶的潜在抑制剂。
