CYP3A4*22 Impairs the Elimination of Ticagrelor, But Has No Significant Effect on the Bioactivation of Clopidogrel or Prasugrel

Abstract

CYP3A enzymes participate in the elimination of ticagrelor and the bioactivation of clopidogrel and prasugrel. We studied the effects of functional CYP3A genetic variants (CYP3A4*22; rs35599367 and CYP3A5*3; rs776746) on the pharmacokinetics and pharmacodynamics of ticagrelor, clopidogrel, and prasugrel. Six healthy volunteers with the CYP3A4*1/*22 and CYP3A5*3/*3 genotype (CYP3A4*22 carriers), eight with the CYP3A4*1/*1 and CYP3A5*1/*3 genotype (CYP3A5 expressors), and 11-13 with the CYP3A4*1/*1 and CYP3A5*3/*3 genotypes (controls) ingested single doses of ticagrelor, clopidogrel, and prasugrel on separate occasions. Ticagrelor area under the plasma concentration-time curve (AUC) was 89% (P = 0.004) higher in CYP3A4*22 carriers than in controls. CYP3A4*22 carriers also showed more pronounced platelet inhibition at 24 hours after ticagrelor ingestion than the controls (43% vs. 21%; P = 0.029). The CYP3A5 genotype did not affect ticagrelor pharmacokinetics. Neither CYP3A5 nor CYP3A4 genotypes significantly affected prasugrel or clopidogrel. In conclusion, the CYP3A4*22 allele markedly impairs ticagrelor elimination enhancing its antiplatelet effect.

Influence of CYP450 Enzymes, CES1, PON1, ABCB1, and P2RY12 Polymorphisms on Clopidogrel Response in Patients Subjected to a Percutaneous Neurointervention

“…However, in our study, CYP3A4 and CYP3A5 did not show a significant role in explaining some of the response variability. Our results resembled those of Holmberg et al who found that neither CYP3A4 nor CYP3A5 genotypes affected clopidogrel area under the concentration-time curve or platelet inhibition in healthy volunteers (30). Furthermore, the G143E polymorphism (rs71647871) described in CES1 was associated with a decreased protein functionality (31).…”

CYP3A4∗22 Genotyping in Clinical Practice: Ready for Implementation?

“…Ticagrelor, clopidogrel, and prasugrel are active platelet aggregation inhibitors metabolized by CYP3A4, used in cardiology and neurology. For ticagrelor, CYP3A4 ∗ 22 carriers showed an 89% higher area-under-the-plasma-concentration-time curve (AUC) and more pronounced platelet inhibition (43% vs. 21%) ( Holmberg et al, 2019 ) ( Supplementary Table 3 ). This increases risk of bleedings ( Becker et al, 2011 ).…”

“…This increases risk of bleedings ( Becker et al, 2011 ). No significant correlation of CYP3A4 ∗ 22 with active metabolites of clopidogrel or prasugrel was found, although the authors stated that differences in clopidogrel and prasugrel pharmacokinetics <50% cannot be ruled out ( Holmberg et al, 2019 ). For sildenafil, metabolized by CYP3A4 in less active compounds, is used in patients with heart failure, CYP3A4 ∗ 22 carriers showed increased dose-adjusted concentrations ( de Denus et al, 2018 ).…”

Spontaneous intermuscular hematoma in a patient receiving ticagrelor and aspirin: A case report

“…Li et al (15) showed that SCLO1B1 and CYP3A4/5 polymorphisms did not affect the pharmacokinetics and pharmacodynamics of ticagrelor treatment in healthy Chinese male subjects. Holmberg et al (16), also showed that although CYP3A4*22 (rs35599367 G>A) impairs elimination, it has no effect on the bioactivation of clopidogrel, and population-based genomics show that there is almost no variation in the frequency of CYP3A4*22 based on populations of diverse ancestry, and thus cannot explain the increased risk of bleeding in Asians. Tatarunas et al (17) demonstrated that the CYP4F2 rs3093135 TT allele has a higher antiplatelet effect of ticagrelor and more frequent nonprocedural bleeding during ticagrelor therapy, as compared with AA and AT variant carriers.…”