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首页> 外文期刊>Frontiers in Pharmacology >Pharmacokinetic and Pharmacogenetic Factors Contributing to Platelet Function Recovery After Single Dose of Ticagrelor in Healthy Subjects
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Pharmacokinetic and Pharmacogenetic Factors Contributing to Platelet Function Recovery After Single Dose of Ticagrelor in Healthy Subjects

机译：替卡格雷在健康受试者中单剂给药后有助于血小板功能恢复的药代动力学和药理学因素

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Objectives: This study aimed to elucidate the contribution of candidate single nucleotide polymorphisms (SNPs) related to pharmacokinetics on the recovery of platelet function after single dose of ticagrelor was orally administered to healthy Chinese subjects. Methods: The pharmacokinetic profiles of ticagrelor and its metabolite AR-C124910XX (M8), and the platelet aggregation (PA), were assessed after 180 mg of single-dose ticagrelor was orally administered to 51 healthy Chinese subjects. Effects of CYP2C19 ~(*) 2, CYP2C19 ~(*) 3, CYP3A5 ~(*) 3, UGT1A1 ~(*) 6, UGT1A1 ~(*) 28, UGT2B7 ~(*) 2, UGT2B7 ~(*) 3, SLCO1B1 388A&G, and SLCO1B1 521T&C, on the pharmacokinetics of ticagrelor and M8, and platelet function recovery were investigated. Results: The time to recover 50% of the maximum drug effect (RT _(50)) ranging from 36 to 126 h with 46.9% CV had a remarkable individual difference and was positively associated with the half-life (t _(1/2)) of M8 ( r = 0.3901, P = 0.0067). The time of peak concentration (T _(max)) of ticagrelor for CYP2C19 ~(*)3 GG homozygotes was significantly higher than that of GA heterozygotes ( P = 0.0027, FDR = 0.0243). Decreased peak concentration (C _(max)) of M8 was significantly associated with SLCO1B1 388A&G A allele ( P = 0.0152, FDR = 0.1368). CYP2C19 ~(*) 2 A was significantly related to decreased C _(max) of M8 ( P = 0.0455, FDR = 0.2048). While, the influence of these nine SNPs on the recovery of platelet function was not significant. Conclusion: Our study suggests that the elimination of M8 is an important factor in determining the recovery of platelet function. Although CYP2C19 and SLCO1B1 genetic variants were related to the pharmacokinetics of ticagrelor or M8, they did not show a significant effect on the platelet function recovery in this study. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03092076 , identifier: NCT03092076
机译：目的：本研究旨在阐明与单药替卡格雷联用给健康中国受试者后，与药代动力学相关的候选单核苷酸多态性（SNP）对血小板功能恢复的贡献。方法：对51位健康的中国受试者口服180mg单剂量的替格瑞洛后，评估替卡格雷及其代谢产物AR-C124910XX（M8）和血小板聚集（PA）的药代动力学特征。 CYP2C19〜（*）2，CYP2C19〜（*）3，CYP3A5〜（*）3，UGT1A1〜（*）6，UGT1A1〜（*）28，UGT2B7〜（*）2，UGT2B7〜（*）3的作用分别对替卡格雷和M8的药代动力学，SLCO1B1 388A＞ G和SLCO1B1 521T＞ C进行了研究，并研究了血小板功能的恢复。结果：恢复36％至126小时的最大药物作用（RT _（50））的时间为36％至126 h，CV为46.9％，个体差异显着且与半衰期呈正相关（t _（1 / 2））的M8（r = 0.3901，P = 0.0067）。 CYP2C19〜（*）3 GG纯合子的替卡格雷的峰值浓度时间（T_（max））显着高于GA杂合子的峰值时间（P = 0.0027，FDR = 0.0243）。 M8的峰浓度降低（C _（max））与SLCO1B1 388A＞ G A等位基因显着相关（P ＝ 0.0152，FDR ＝ 0.1368）。 CYP2C19〜（*）2 A与M8的C _（max）降低显着相关（P = 0.0455，FDR = 0.2048）。同时，这九个SNP对血小板功能恢复的影响并不显着。结论：我们的研究表明，消除M8是决定血小板功能恢复的重要因素。尽管CYP2C19和SLCO1B1遗传变异与替卡格雷或M8的药代动力学相关，但在本研究中它们并未显示出对血小板功能恢复的显着影响。临床试验注册：https://clinicaltrials.gov/ct2/show/NCT03092076，标识符：NCT03092076

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