Itkonen Matti K, Tornio Aleksi, Neuvonen Mikko, Neuvonen Pertti J, Niemi Mikko, Backman Janne T
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Drug Metab Dispos. 2015 Nov;43(11):1655-60. doi: 10.1124/dmd.115.065938. Epub 2015 Sep 1.
Simvastatin and clopidogrel are commonly used together in the treatment of cardiovascular diseases. Organic anion transporting polypeptide (OATP) 1B1 activity markedly affects the hepatic uptake of simvastatin acid, whereas both simvastatin and simvastatin acid are sensitive to changes in cytochrome P450 3A4 activity. Clopidogrel and its metabolites inhibit OATP1B1 and CYP3A4 in vitro. We studied the effect of clopidogrel on the pharmacokinetics of simvastatin in a randomized crossover study. Twelve healthy volunteers ingested either a dose of placebo (control) or 300 mg of clopidogrel on day 1 and 75 mg on days 2 and 3. Simvastatin 40 mg was administered 1 hour after placebo and after clopidogrel on days 1 and 3. Plasma drug concentrations were measured for up to 12 hours. Clopidogrel 300 mg (day 1) increased the concentrations of simvastatin and simvastatin acid during the absorption phase. After clopidogrel 300 mg, the area under the concentration time curve (AUC) of simvastatin from 0 to 2 hours was 156% (P = 0.02) and its AUC(0-12 hours) was 132% (P = 0.08) of that during placebo, whereas the AUC(0-2 hours) and the AUC(0-12 hours) of simvastatin acid were 148% (P = 0.04) and 112% (P = 0.52) of control. Clopidogrel 75 mg (day 3) had no significant effect on the pharmacokinetic variables of simvastatin or simvastatin acid compared with placebo. The effect of clopidogrel seemed independent of the SLCO1B1 c.521T>C genotype. In conclusion, as clopidogrel did not have significant effects on the total exposure to simvastatin or simvastatin acid, clopidogrel does not seem to inhibit OATP1B1 or CYP3A4 to a clinically relevant extent.
辛伐他汀和氯吡格雷常用于心血管疾病的治疗。有机阴离子转运多肽（OATP）1B1的活性显著影响辛伐他汀酸的肝脏摄取，而辛伐他汀和辛伐他汀酸对细胞色素P450 3A4活性的变化均敏感。氯吡格雷及其代谢产物在体外可抑制OATP1B1和CYP3A4。我们在一项随机交叉研究中探讨了氯吡格雷对辛伐他汀药代动力学的影响。12名健康志愿者在第1天服用一剂安慰剂（对照）或300 mg氯吡格雷，在第2天和第3天服用75 mg氯吡格雷。在第1天和第3天，在服用安慰剂和氯吡格雷1小时后给予40 mg辛伐他汀。测量血浆药物浓度长达12小时。第1天服用300 mg氯吡格雷在吸收期增加了辛伐他汀和辛伐他汀酸的浓度。服用300 mg氯吡格雷后，辛伐他汀从0至2小时的浓度-时间曲线下面积（AUC）为安慰剂期间的156%（P = 0.02），其AUC（0 - 12小时）为安慰剂期间的132%（P = 0.08），而辛伐他汀酸的AUC（0 - 2小时）和AUC（0 - 12小时）分别为对照的148%（P = 0.04）和112%（P = 0.52）。与安慰剂相比，第3天服用75 mg氯吡格雷对辛伐他汀或辛伐他汀酸的药代动力学变量无显著影响。氯吡格雷的作用似乎与SLCO1B1 c.521T>C基因型无关。总之，由于氯吡格雷对辛伐他汀或辛伐他汀酸的总暴露量无显著影响，氯吡格雷似乎不会在临床相关程度上抑制OATP1B1或CYP3A4。
