title: No Effect of SLCO1B1 and CYP3A4/5 Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Ticagrelor in Healthy Chinese Male Subjects.
abstract: Ticagrelor is a direct-acting P2Y12 receptor antagonist. It is rapidly absorbed and partly metabolized to the active metabolite AR-C124910XX by CYP3A4 and CYP3A5. Three genetic loci (SLCO1B1, CYP3A4, and UGT2B7) were reported to affect ticagrelor pharmacokinetics. This study aimed to investigate the possible effects of SLCO1B1 and CYP3A4/5 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy Chinese male volunteers. Eighteen healthy male volunteers who participated in pharmacogenetics study of ticagrelor were genotyped for SLCO1B1 rs113681054, SLCO1B1*5 (rs4149056), CYP3A4*1G (rs2242480), and CYP3A5*3 (rs776746). All subjects received a single 180 mg loading dose of ticagrelor and then series blood samples were collected from 0 to 48 h. Plasma concentrations of ticagrelor and AR-C124910XX were determined by the high performance liquid chromatography-tandem mass spectrometry method. Inhibition in platelet aggregation (IPA) was assessed and the area under the time-effect curve (AUEC) for the IPA was calculated as pharmacodynamic parameters. No significant difference in ticagrelor pharmacokinetics among genotypes of the two genes was observed. The AUEC did not differ significantly among genotypes of candidate single nucleotide polymorphisms (SNPs). Our data suggest that common genetic variants in SLCO1B1 and CYP3A4/5 may have no effect on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy Chinese volunteers.
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University.
authors.forename: Mupeng
authors.initials: M
authors.lastname: Li
authors.forename: Yaodong
authors.initials: Y
authors.lastname: Hu
authors.forename: Huilan
authors.initials: H
authors.lastname: Li
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Wen
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Hu
authors.forename: Daoyu
authors.initials: D
authors.lastname: Zhang
authors.forename: Yanjiao
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Xiao
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Chen
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D044466:Asian People / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005838:Genotype; D064368:Healthy Volunteers; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1 / Q000235:genetics*; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide; D058919:Purinergic P2 Receptor Antagonists / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D000077486:Ticagrelor
chemical_list: C561701:AR C124910XX; D027381:Liver-Specific Organic Anion Transporter 1; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; C503999:SLCO1B1 protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000077486:Ticagrelor; D000241:Adenosine