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CYP3A4*22 may increase bleeding risk in ticagrelor users


The conventional treatment for acute coronary syndromes (ACS) includes percutaneous coronary intervention with stent placement requiring dual antiplatelet therapy with acetylsalicylic acid (ASA) and an antiplatelet drug (clopidogrel, prasugrel or ticagrelor). Ticagrelor outweighs some of the limitations of clopidogrel and prasugrel: It does not need metabolic activation and binds rapidly and reversibly to the P2Y12 receptors.1 Compared with clopidogrel, ticagrelor has greater and more consistent inhibition of platelet aggregation, and its effect does not appear to be influenced by single-nucleotide variants (SNV) in CYP2C19 or ABCB1.1

Ticagrelor is primarily metabolized in the liver by CYP3A4 and CYP3A5 enzymes to its active and approximately equipotent metabolite AR-C124910XX,1 suggesting that genetic variation in these enzymes may affect ticagrelor metabolism. In patients with ACS, SLCO1B1 (rs113681054), CYP3A4 (rs62471956, rs56324128) and UGT2B7 (rs61361928) variants were associated with ticagrelor pharmacokinetics but not with clinical outcomes.2 Results on effects of CYP4F2 rs3093135 variant are contradicting.3, 4 There is no established explanation on how CYP4F2 rs3093135 variant might affect platelet function during antiplatelet therapy.3 CYP4F2 enzyme is involved in synthesis of 20-hydroxyeicosatetraenoic acid which may have an antiplatelet effect.3 It also participates in metabolism of vitamin K and might, thus, affect synthesis of vitamin K dependent coagulation factors.5 In healthy Chinese males, SLCO1B1 (rs113681054, rs4149056), CYP3A4*1G (rs2242480) or CYP3A5*3 (rs776746) variants did not affect ticagrelor pharmacokinetics or pharmacodynamics.6 Another study in healthy volunteers found that CYP3A4*22 (rs35599367) carriers had elevated plasma concentrations of ticagrelor and AR-C124910XX as well as a more pronounced platelet inhibition than non-carriers, whereas the CYP3A5*3 (rs776746) allele was not associated with ticagrelor pharmacokinetics.7

This study utilized Finnish biobanks and national health registries to investigate the association of CYP3A4*22 (rs35599367), CYP3A5*3 (rs776746) and CYP4F2 rs3093135 variants with incidence of bleeding events in ticagrelor users.


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