Nie Shanshan, Chen Kaifeng, Guo Chengxian, Pei Qi, Zou Chan, Yao Liangyuan, Yuan Hongbo, Zhao Xia, Xie Ran, He Xu, Huang Jie, Yang Guoping
Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, China.
Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, China.
Front Pharmacol. 2022 Feb 25;12:797278. doi: 10.3389/fphar.2021.797278. eCollection 2021.
Ticagrelor belongs to a new class of P2Y receptor inhibitor that has been widely used for antiplatelet therapy. This study aimed to explore the effect of single nucleotide polymorphisms (SNPs) in metabolic enzymes, transporters, and other relevant variants on the pharmacokinetics (PK) of ticagrelor and its active metabolite, AR-C124910XX. The study population comprised 68 healthy Chinese volunteers who were enrolled in a ticagrelor bioequivalence clinical trial. The PK profile of ticagrelor was evaluated after orally administering a single 90-mg dose of ticagrelor in tablet form. The plasma concentrations of ticagrelor and AR-C124910XX were determined through liquid chromatography-tandem mass spectrometry. Plasma DNA samples were used to explore the effect of gene polymorphisms on the PK of ticagrelor and AR-C124910XX with whole-exome sequencing. Female participants had a higher maximum plasma concentration/weight ratio ( /; < 0.001) and a shorter half-life ( ; < 0.05) for ticagrelor than their male counterparts. In addition, a higher area under the curve/weight ratio (AUC/; < 0.001), and longer ( < 0.001) and time to reach the maximum plasma concentration ( ; < 0.001), as well as a lower apparent drug clearance (CL/F; < 0.001), were observed among healthy volunteers in the fed trial compared to those enrolled in the fasting trial. For AR-C124910XX, higher / ( < 0.001) and AUC/ ( < 0.001) but lower CL/F ( < 0.001) and apparent volume of distribution ( /F; < 0.001) were observed among female participants. Healthy volunteers enrolled in the fasting trial exhibited higher / ( < 0.001) and AUC/ ( < 0.01), shorter ( < 0.001), and lower CL/F ( < 0.001) and /F ( < 0.001) than those enrolled in the fed trial. Upon confirmation through multivariate analysis, the rs2074900 A/A carriers were associated with higher / and AUC/ and lower CL/F and /F than the rs2074900 A/G and G/G carriers. This study is the first to show that the rs2074900 SNP had a remarkable effect on ticagrelor PK, which is significant since it adds to the limited pharmacogenetic information on ticagrelor.
替格瑞洛属于一类新型的P2Y受体抑制剂，已被广泛用于抗血小板治疗。本研究旨在探讨代谢酶、转运体及其他相关变异中的单核苷酸多态性（SNP）对替格瑞洛及其活性代谢产物AR-C124910XX药代动力学（PK）的影响。研究人群包括68名健康中国志愿者，他们参与了替格瑞洛生物等效性临床试验。口服单剂量90mg片剂替格瑞洛后，评估其PK特征。通过液相色谱-串联质谱法测定替格瑞洛和AR-C124910XX的血浆浓度。利用血浆DNA样本通过全外显子测序探讨基因多态性对替格瑞洛和AR-C124910XX PK的影响。女性参与者的替格瑞洛最大血浆浓度/体重比（/；<0.001）较高，半衰期较短（；<0.05）。此外，与空腹试验的健康志愿者相比，进食试验的健康志愿者的曲线下面积/体重比（AUC/；<0.001）更高，达峰时间（<0.001）和达到最大血浆浓度的时间（；<0.001）更长，表观药物清除率（CL/F；<0.001）更低。对于AR-C124910XX，女性参与者的/（<0.001）和AUC/（<0.001）较高，但CL/F（<0.001）和表观分布容积（/F；<0.001）较低。与进食试验的健康志愿者相比，空腹试验的健康志愿者的/（<0.001）和AUC/（<0.01）较高，达峰时间较短（<0.001），CL/F（<0.001）和/F（<0.001）较低。经多变量分析确认，rs2074900 A/A携带者与rs2074900 A/G和G/G携带者相比，/和AUC/较高，CL/F和/F较低。本研究首次表明rs2074900 SNP对替格瑞洛的PK有显著影响，这很重要，因为它增加了关于替格瑞洛有限的药物遗传学信息。
