Effect of CYP3A4(∗)1G and CYP3A5(∗)3 Polymorphisms on Pharmacokinetics and Pharmacodynamics of Ticagrelor in Healthy Chinese Subjects.
Effect of CYP3A4(∗)1G and CYP3A5(∗)3 Polymorphisms on Pharmacokinetics and Pharmacodynamics of Ticagrelor in Healthy Chinese Subjects.
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DOI：
10.3389/fphar.2017.00176
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发表时间：
2017
影响因子：
5.6
通讯作者：
Miao L
中科院分区：
文献类型：
--
作者：
Liu S;Shi X;Tian X;Zhang X;Sun Z;Miao L
替格瑞洛是第一个可逆的，直接作用的，有效的P2 Y12受体拮抗剂在急性冠状动脉综合征的管理。它被迅速吸收和广泛代谢。主要活性代谢产物AR-C124910 XX以大致相等的效力拮抗P2 Y12受体。替格瑞洛代谢为AR-C124910 XX涉及CYP 3A 4和CYP 3A 5。CYP 3A基因多态性已被广泛研究，其中CYP 3A 4 - 1G（g.20230G>A，rs 2242480）和CYP 3A 5 - 13（g.6986A>G，rs776746）是中国人群中最重要的单核苷酸多态性。人类志愿者和患者中CYP 3A 4和CYP 3A 5表达的遗传差异可能会影响替格瑞洛或AR-C124910 XX的体内清除率，从而导致后续患者应答的变化。因此，本研究旨在探讨CYP 3A 4 <$1G和CYP 3A 5 <$3多态性对替格瑞洛在中国健康受试者中的药代动力学和药效学的影响。结果表明，CYP 3A 4 β 1G多态性显著影响AR-C124910 XX的药代动力学，在通过增加CYP 3A 4活性影响替格瑞洛药代动力学方面，它可能比CYP 3A 5 β 3更重要。然而，CYP 3A 4 β 1G多态性对AR-C124910 XX血浆水平的显著影响并未转化为对血小板聚集抑制的可检测影响。因此，似乎没有必要根据CYP 3A 4或3A 5基因型调整替格瑞洛的剂量。
Ticagrelor is the first reversible, direct-acting, potent P2Y12 receptor antagonist in management of acute coronary syndromes. It is rapidly absorbed and extensively metabolized. AR-C124910XX, the major active metabolite, antagonizes the P2Y12 receptor at approximately equal potency. The metabolism of ticagrelor to AR-C124910XX involves CYP3A4 and CYP3A5. CYP3A polymorphisms have been well documented, and CYP3A4∗1G (g.20230G>A, rs2242480) and CYP3A5∗3 (g.6986A>G, rs776746) are the most important single nucleotide polymorphisms in Chinese. Genetic differences in CYP3A4 and CYP3A5 expression in human volunteers and patients might affect the clearance of ticagrelor or AR-C124910XX in vivo resulting in subsequent variable patient response. Thus, this study is designed to explore the effects of CYP3A4∗1G and CYP3A5∗3 polymorphisms on the pharmacokinetics and pharmcodynamics of ticagrelor in healthy Chinese subjects. The results indicated that the CYP3A4∗1G polymorphism significantly influenced the pharmacokinetics of AR-C124910XX, and it may be more important than CYP3A5∗3 with respect to influencing ticagrelor pharmacokinetics by increasing CYP3A4 activity. However, the significant effect of CYP3A4∗1G polymorphism on AR-C124910XX plasma levels did not translate into detectable effect on inhibition of platelet aggregation. Therefore, it seems not necessary to adjust the dosage of ticagrelor according to the CYP3A4 or 3A5 genotype.