Pharmacokinetic and Pharmacogenetic Factors Contributing to Platelet Function Recovery After Single Dose of Ticagrelor in Healthy Subjects
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...
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Frontiers Media S.A.
2019-03-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2019.00209/full |
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| author | Qian Zhu Qian Zhu Qian Zhu Wanping Zhong Wanping Zhong Xipei Wang Liping Mai Guodong He Jiyan Chen Lan Tang Shuwen Liu Weihua Lai Shilong Zhong Shilong Zhong Shilong Zhong |
| author_facet | Qian Zhu Qian Zhu Qian Zhu Wanping Zhong Wanping Zhong Xipei Wang Liping Mai Guodong He Jiyan Chen Lan Tang Shuwen Liu Weihua Lai Shilong Zhong Shilong Zhong Shilong Zhong |
| author_sort | Qian Zhu |
| collection | DOAJ |
| description | 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 (RT50) ranging from 36 to 126 h with 46.9% CV had a remarkable individual difference and was positively associated with the half-life (t1/2) of M8 (r = 0.3901, P = 0.0067). The time of peak concentration (Tmax) of ticagrelor for CYP2C19*3 GG homozygotes was significantly higher than that of GA heterozygotes (P = 0.0027, FDR = 0.0243). Decreased peak concentration (Cmax) 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 Cmax 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 |
| first_indexed | 2024-12-19T05:13:42Z |
| format | Article |
| id | doaj.art-9fdba488ba8846799f89397f387ab628 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-19T05:13:42Z |
| publishDate | 2019-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-9fdba488ba8846799f89397f387ab6282022-12-21T20:34:44ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122019-03-011010.3389/fphar.2019.00209434651Pharmacokinetic and Pharmacogenetic Factors Contributing to Platelet Function Recovery After Single Dose of Ticagrelor in Healthy SubjectsQian Zhu0Qian Zhu1Qian Zhu2Wanping Zhong3Wanping Zhong4Xipei Wang5Liping Mai6Guodong He7Jiyan Chen8Lan Tang9Shuwen Liu10Weihua Lai11Shilong Zhong12Shilong Zhong13Shilong Zhong14Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, ChinaDepartment of Pharmacy of Guangdong Provincial People's Hospital, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, ChinaSchool of Pharmaceutical Sciences, Southern Medical University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, ChinaDepartment of Pharmacy of Guangdong Provincial People's Hospital, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, ChinaDepartment of Pharmacy of Guangdong Provincial People's Hospital, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, ChinaDepartment of Pharmacy of Guangdong Provincial People's Hospital, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, ChinaSchool of Pharmaceutical Sciences, Southern Medical University, Guangzhou, ChinaSchool of Pharmaceutical Sciences, Southern Medical University, Guangzhou, ChinaDepartment of Pharmacy of Guangdong Provincial People's Hospital, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, ChinaDepartment of Pharmacy of Guangdong Provincial People's Hospital, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, ChinaSchool of Pharmaceutical Sciences, Southern Medical University, Guangzhou, ChinaObjectives: 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 (RT50) ranging from 36 to 126 h with 46.9% CV had a remarkable individual difference and was positively associated with the half-life (t1/2) of M8 (r = 0.3901, P = 0.0067). The time of peak concentration (Tmax) of ticagrelor for CYP2C19*3 GG homozygotes was significantly higher than that of GA heterozygotes (P = 0.0027, FDR = 0.0243). Decreased peak concentration (Cmax) 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 Cmax 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: NCT03092076https://www.frontiersin.org/article/10.3389/fphar.2019.00209/fullgenetic variantshealthy subjectspharmacokineticsrecovery of platelet functionticagrelor |
| spellingShingle | Qian Zhu Qian Zhu Qian Zhu Wanping Zhong Wanping Zhong Xipei Wang Liping Mai Guodong He Jiyan Chen Lan Tang Shuwen Liu Weihua Lai Shilong Zhong Shilong Zhong Shilong Zhong Pharmacokinetic and Pharmacogenetic Factors Contributing to Platelet Function Recovery After Single Dose of Ticagrelor in Healthy Subjects Frontiers in Pharmacology genetic variants healthy subjects pharmacokinetics recovery of platelet function ticagrelor |
| title | Pharmacokinetic and Pharmacogenetic Factors Contributing to Platelet Function Recovery After Single Dose of Ticagrelor in Healthy Subjects |
| title_full | Pharmacokinetic and Pharmacogenetic Factors Contributing to Platelet Function Recovery After Single Dose of Ticagrelor in Healthy Subjects |
| title_fullStr | Pharmacokinetic and Pharmacogenetic Factors Contributing to Platelet Function Recovery After Single Dose of Ticagrelor in Healthy Subjects |
| title_full_unstemmed | Pharmacokinetic and Pharmacogenetic Factors Contributing to Platelet Function Recovery After Single Dose of Ticagrelor in Healthy Subjects |
| title_short | Pharmacokinetic and Pharmacogenetic Factors Contributing to Platelet Function Recovery After Single Dose of Ticagrelor in Healthy Subjects |
| title_sort | pharmacokinetic and pharmacogenetic factors contributing to platelet function recovery after single dose of ticagrelor in healthy subjects |
| topic | genetic variants healthy subjects pharmacokinetics recovery of platelet function ticagrelor |
| url | https://www.frontiersin.org/article/10.3389/fphar.2019.00209/full |
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