Effect of CYP3A4∗1G and CYP3A5∗3 Polymorphisms on Pharmacokinetics and Pharmacodynamics of Ticagrelor in Healthy Chinese Subjects

Abstract

Ticagrelor is the first reversible, direct-acting, potent P2Y12 receptor antagonist in management of acute coronary syndromes. It is rapidly absorbed and extensively metabolized. AR-C124910XX, the major active metabolite, antagonizes the P2Y12 receptor at approximately equal potency. The metabolism of ticagrelor to AR-C124910XX involves CYP3A4 and CYP3A5. CYP3A polymorphisms have been well documented, and CYP3A4∗1G (g.20230G>A, rs2242480) and CYP3A5∗3 (g.6986A>G, rs776746) are the most important single nucleotide polymorphisms in Chinese. Genetic differences in CYP3A4 and CYP3A5 expression in human volunteers and patients might affect the clearance of ticagrelor or AR-C124910XX in vivo resulting in subsequent variable patient response. Thus, this study is designed to explore the effects of CYP3A4∗1G and CYP3A5∗3 polymorphisms on the pharmacokinetics and pharmcodynamics of ticagrelor in healthy Chinese subjects. The results indicated that the CYP3A4∗1G polymorphism significantly influenced the pharmacokinetics of AR-C124910XX, and it may be more important than CYP3A5∗3 with respect to influencing ticagrelor pharmacokinetics by increasing CYP3A4 activity. However, the significant effect of CYP3A4∗1G polymorphism on AR-C124910XX plasma levels did not translate into detectable effect on inhibition of platelet aggregation. Therefore, it seems not necessary to adjust the dosage of ticagrelor according to the CYP3A4 or 3A5 genotype.

Pharmacokinetic and Pharmacogenetic Factors Contributing to Platelet Function Recovery After Single Dose of Ticagrelor in Healthy Subjects

“…CYP3A4 * 1G is in strong linkage disequilibrium with CYP3A5 * 3 (Fukushima-Uesaka et al, 2004 ). However, the CYP3A4 * 1G polymorphism significantly associated with the pharmacokinetics of M8 did not influence the IPA (Liu et al, 2017 ), and the platelet function in response to ticagrelor also is not affected by CYP2C19, ABCB1, P2RY12, P2RY1 , and ITGB3 genotypes (Storey et al, 2009 ; Tantry et al, 2010 ; Wallentin et al, 2010 ). To investigate the influence of genetic variants related to the ticagrelor pharmacokinetics on the variability of the recovery of the platelet function in Chinese volunteers after they received a single dose of ticagrelor, we selected candidate SNPs in CYP2C19, CYP3A5, UGT1A1, UGT2B7 , and SLCO1B1 , which exhibited a relatively high variant allele frequency in Chinese; these SNPs were also documented in pharmacokinetics (Jada et al, 2007 ; Kim et al, 2008 ; Wallentin et al, 2010 ; Wang et al, 2012 ; Lu et al, 2015 ; Varenhorst et al, 2015 ).…”

Influence of FMO3 and CYP3A4 Polymorphisms on the Pharmacokinetics of Teneligliptin in Humans

“…The effect of rs2242480 ( CYP3A4 *1G) polymorphism on CYP3A4 functions is controversial ( Hu et al, 2007 ; Liu et al, 2017 ; Lolita et al, 2020 ). Current knowledge indicates that the effect of polymorphism on CYP3A4 activity is dependent on the substrate ( Stresser et al, 2000 ).…”

Cytochrome P450 3A Enzymes Are Key Contributors for Hepatic Metabolism of Bufotalin, a Natural Constitute in Chinese Medicine Chansu

“…However, the catalytic efficacy and the kinetic behaviors of BFT 5β-hydroxylation are quite different in CYP3A4 and CYP3A5. Taking into account that CYP3A enzymes are the predominant contributors in hepatic metabolism of BFT, the individual discrepancy in BFT metabolism may be very significant due to the large inter-individual differences in the expression and function of CYP3A (Liu et al, 2017). Although the levels of CYP3A4 in liver is generally higher than CYP3A5, but in some cases, the levels of CYP3A5 in given populations (such as African) may higher than that of CYP3A4 (Westlind-Johnsson et al, 2003; Lu et al, 2012).…”