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Effect of CYP4F2 Polymorphisms on Ticagrelor Pharmacokinetics in Healthy Chinese Volunteers

Background: Ticagrelor belongs to a new class of P2Y(12) 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...

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Detalles Bibliográficos
Autores principales: Nie, Shanshan, Chen, Kaifeng, Guo, Chengxian, Pei, Qi, Zou, Chan, Yao, Liangyuan, Yuan, Hongbo, Zhao, Xia, Xie, Ran, He, Xu, Huang, Jie, Yang, Guoping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8915292/
https://www.ncbi.nlm.nih.gov/pubmed/35280252
http://dx.doi.org/10.3389/fphar.2021.797278
Descripción
Sumario:Background: Ticagrelor belongs to a new class of P2Y(12) 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. Methods: 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. Results: Female participants had a higher maximum plasma concentration/weight ratio (C (max)/W; p < 0.001) and a shorter half-life (T (1/2); p < 0.05) for ticagrelor than their male counterparts. In addition, a higher area under the curve/weight ratio (AUC/W; p < 0.001), and longer T (1/2) (p < 0.001) and time to reach the maximum plasma concentration (T (max); p < 0.001), as well as a lower apparent drug clearance (CL/F; p < 0.001), were observed among healthy volunteers in the fed trial compared to those enrolled in the fasting trial. For AR-C124910XX, higher C (max)/W (p < 0.001) and AUC/W (p < 0.001) but lower CL/F (p < 0.001) and apparent volume of distribution (V (d)/F; p < 0.001) were observed among female participants. Healthy volunteers enrolled in the fasting trial exhibited higher C (max)/W (p < 0.001) and AUC/W (p < 0.01), shorter T (max) (p < 0.001), and lower CL/F (p < 0.001) and V (d)/F (p < 0.001) than those enrolled in the fed trial. Upon confirmation through multivariate analysis, the CYP4F2 rs2074900 A/A carriers were associated with higher C (max)/W and AUC/W and lower CL/F and V (d)/F than the CYP4F2 rs2074900 A/G and G/G carriers. Conclusion: This study is the first to show that the CYP4F2 rs2074900 SNP had a remarkable effect on ticagrelor PK, which is significant since it adds to the limited pharmacogenetic information on ticagrelor.