基于代谢酶、转运体和靶标基因多态性对替格瑞洛药动学及药效学影响的研究

Ticagrelor is a new promising direct-acting, potent P2Y12 receptor antagonist in management of acute coronary syndromes(ACS). It is primarily metabolized by cytochrome P450 (CYP) 3A4 and 3A5 to the active metabolite, AR-C124910XX, which exhibits almost the same potency in antiplatelet effect as the parent drug, and systemic exposure to ARC124910XX is ~30-40% that of the parent compound. Genome-wide association study showed that genetic variations in OATP1B1 affects the levels of ticagrelor and AR-C124910XX in vivo, wherase, evidence is limited about whether the OATP1B1 is responsible for hepatic uptake of ticagrelor. The CYP3A4*1G and CYP3A5*3 alleles are important in Chinese subjects clinically because of their relatively high frequency. The present study aimes at investigating whether OATP1B1 is responsible for the hepatic uptake of ticagrelor as well as exploring the effects of CYP3A4*1G and OATP1B1 ploymorphisms on its pharmacokinetics and pharmacodynamics in healthy Chinese subjects and patients with ACS; To establish a model that comprises the genetic and non-genetic factors on metabolism of ticagrelor and platelet response (VASP-P and IPA),expecting to provide reference for ticagrelor individualized therapy in clinic.

替格瑞洛——新型的治疗急性冠脉综合征的药物。其吸收进入人体后，在肝脏可被CYP3A4和3A5代谢生成与原药活性相当的代谢产物AR-C124910XX，该代谢物在体内的暴露量为原药的30%~40%。全基因组关联研究表明肝摄取转运体OATP1B1遗传变异会影响替格瑞洛及AR-C124910XX在体内的暴露量，然而并没有直接证据支持OATP1B1参与了替格瑞洛的肝摄取。CYP3A4*1G及CYP3A5*3是中国人群比较重要的遗传变异。本课题拟首先在细胞水平考察OATP1B1是否参与替格瑞洛的肝摄取，在此基础上进一步在健康志愿者及冠心病患者中考察CYP3A4*1G及OATP1B1遗传变异对替格瑞洛药动学及药效学发挥的影响；最后建立冠心病人群中CYP3A4、OATP1B1等基因及临床因素对替格瑞洛代谢及血小板活性影响模型，以期为其临床合理使用提供依据。

替格瑞洛作为新型的治疗急性冠脉综合征的药物，其吸收进入人体后，在肝脏可被CYP3A4和3A5代谢生成与原药活性相当的代谢产物AR-C124910XX，该代谢物在体内的暴露量为原药的30%~40%。全基因组关联研究表明肝摄取转运体OATP1B1遗传变异会影响替格瑞洛及AR-C124910XX在体内的暴露量，然而并没有直接证据支持OATP1B1参与了替格瑞洛的肝摄取。CYP3A4*1G及CYP3A5*3是中国人群比较重要的遗传变异，由于遗传变异导致上述酶活性改变对替格瑞洛的药动学和药效学影响目前鲜有报道。本课题利用过表达OATP1B1转运体细胞系统探讨了其对替格瑞洛及其代谢产物的体外摄取作用，实验结果表明：OATP1B1参与了替格瑞洛和其非活性代谢产物的体外摄取。在此基础上进一步在健康志愿者体内探索了SLCO1B1 A>388G，SLCO1B1 T>521C，CYP3A4*1G和CYP3A5*3对替格瑞洛及其活性代谢产物AR-C124910XX药动学和药效学影响。结果表明：OATP1B1 388AA（n=11）型志愿者体内替格瑞洛的血浆Cmax，AUC0-t及AUC0-∞要显著高于OATP1B1 388AG（n=3），但SLCO1B1 A>388G基因型对AR-C124910XX的主要药动学参数无显著影响，然而其对替格瑞洛对药动学影响并未转变为药效学影响。遗憾的是此14例志愿者中SLCO1B1T>521C遗传变异仅有一例，尚无法进行进一步分析，SLCO1B1T>521C遗传变异对其药动学和药效学的影响尚需进行进一步研究；CYP3A4*1G基因多态性通过增加CYP3A4酶活性显著影响了AR-C124910XX的药动学，并且CYP3A4比CYP3A5在AR-C124910XX生成中发挥了更加重要的作用。然而CYP3A4*1G基因多态性对AR-C124910XX血浆水平的影响并未转变成对血小板聚集水平的影响，因此对于替格瑞洛来说，根据CYP3A4或CYP3A5基因型调整剂量似乎并没有必要。进一步用群体药动学的方法构建替格瑞洛及AR-C124910XX在中国健康志愿者中的群体药动学模型，确证了CYP3A4*1G在替格瑞洛药动学中的作用。群体药动学模拟结果表明，30mg维持剂量（MD）和12h给药间隔的给药方案可产生预期的抗血小板反应，且出血率和心血管风险较低。