Kim Ho-Sook, Lim Younghae, Oh Minkyung, Ghim Jong-Lyul, Kim Eun-Young, Kim Dong-Hyun, Shin Jae-Gook
Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine.
Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan, South Korea.
Br J Clin Pharmacol. 2016 Feb;81(2):301-12. doi: 10.1111/bcp.12794. Epub 2015 Dec 28.
The primary objective of the present study was to evaluate the pharmacokinetic and pharmacodynamic interactions between clopidogrel and cilostazol in relation to the CYP2C19 and CYP3A5 genotypes.
In a randomized, three-way crossover study, 27 healthy subjects were administered clopidogrel (300 mg), cilostazol (100 mg) or clopidogrel + cilostazol orally. Plasma concentrations of clopidogrel, cilostazol and their active metabolites (clopidogrel thiol metabolite, 3,4-dehydrocilostazol and 4″-trans-hydroxycilostazol), and adenosine diphosphate-induced platelet aggregation were measured for pharmacokinetic and pharmacodynamic assessment.
The area under the plasma concentration-time curve (AUC) of the active thiol metabolite of clopidogrel was highest in the CYP2C19 extensive metabolizers (EM) and lowest in the poor metabolizers (PM). Cilostazol decreased the thiol metabolite AUC by 29% in the CYP3A5*1/3 genotype [geometric mean ratio (GMR) 0.71; 90% confidence interval (CI) 0.58, 0.86; P = 0.020] but not in the CYP3A53/3 genotype (GMR 0.93; 90% CI 0.80, 1.10; P = 0.446). Known effects of the CYP2C19 and CYP3A5 genotypes on the exposure of cilostazol and its metabolites were observed but there was no significant difference in the AUC of cilostazol and 3,4-dehydrocilostazol between cilostazol and clopidogrel + cilostazol. The inhibition of platelet aggregation from 4 h to 24 h (IPA4-24 ) following the administration of clopidogrel alone was highest in the CYP2C19 EM genotype and lowest in the CYP2C19 PM genotype (59.05 ± 18.95 vs. 36.74 ± 13.26, P = 0.023). However, the IPA of the CYP2C19 PM following co-administration of clopidogrel and cilostazol was comparable with that of the CYP2C19 EM and intermediate metabolizers (IM) only in CYP3A53/*3 subjects.
The additive antiplatelet effect of cilostazol plus clopidogrel is maximized in subjects with both the CYP2C19 PM and CYP3A5*3/3 genotypes because of a lack of change of clopidogrel thiol metabolite exposure in CYP3A53/3 as well as the highest cilostazol IPA in CYP2C19 PM and CYP3A53/*3 subjects.
本研究的主要目的是评估氯吡格雷与西洛他唑在CYP2C19和CYP3A5基因分型方面的药代动力学和药效学相互作用。
在一项随机、三交叉研究中，27名健康受试者口服给予氯吡格雷（300毫克）、西洛他唑（100毫克）或氯吡格雷+西洛他唑。测量氯吡格雷、西洛他唑及其活性代谢物（氯吡格雷硫醇代谢物、3,4-脱氢西洛他唑和4''-反式羟基西洛他唑）的血浆浓度以及二磷酸腺苷诱导的血小板聚集，以进行药代动力学和药效学评估。
氯吡格雷活性硫醇代谢物的血浆浓度-时间曲线下面积（AUC）在CYP2C19广泛代谢者（EM）中最高，在慢代谢者（PM）中最低。在CYP3A5*1/3基因型中，西洛他唑使硫醇代谢物AUC降低了29%[几何平均比值（GMR）0.71；90%置信区间（CI）0.58，0.86；P = 0.020]，而在CYP3A53/3基因型中未降低（GMR 0.93；90% CI 0.80，1.10；P = 0.446）。观察到CYP2C19和CYP3A5基因分型对西洛他唑及其代谢物暴露的已知影响，但西洛他唑和氯吡格雷+西洛他唑之间西洛他唑和3,4-脱氢西洛他唑的AUC无显著差异。单独给予氯吡格雷后4小时至24小时的血小板聚集抑制率（IPA4-24）在CYP2C19 EM基因型中最高，在CYP2C19 PM基因型中最低（59.05±18.95对36.74±13.26，P = 0.023）。然而，仅在CYP3A53/*3受试者中，氯吡格雷与西洛他唑联合给药后CYP2C19 PM的IPA与CYP2C19 EM和中间代谢者（IM）相当。
由于在CYP3A5*3/3中氯吡格雷硫醇代谢物暴露无变化，以及在CYP2C19 PM和CYP3A53/3受试者中西洛他唑IPA最高，西洛他唑加氯吡格雷的相加抗血小板作用在CYP2C19 PM和CYP3A53/*3基因型受试者中最大化。
