Impacts of pregnane X receptor and cytochrome P450 oxidoreductase gene polymorphisms on trough concentrations of apixaban in patients with non-valvular atrial fibrillation

Abstract

Purpose: We examined the impact of polymorphisms in genes encoding cytochrome P450 (CYP) 3A5 (gene code CYP3A5), P-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2), cytochrome P450 oxidoreductase (POR) and pregnane X receptor (PXR; NR1I2) on the steady-state trough concentrations (C 0h ) of apixaban.Methods: The analyses included 86 patients with non-valvular atrial brillation (NVAF) undergoing AF catheter ablation. The CYP3A5*3; ABCG2 421C>A; ABCB1 1236C>T, 2677G>A/T, 3435C>T, and 2482-2236G>A; NR1I2 11156A>C, 11193T>C, and 8055C>T; and POR*28 genotypes were determined. The combination of the noted NR1I2 genotypes determined the PXR*1B haplotype.Results: Stepwise selection multiple linear regression analyses demonstrated that decreased creatinine clearance and the PXR*1B/*1B genotype correlated with increased apixaban C 0h , while the presence of the POR*28 allele correlated with decreased C 0h (partial R 2 = 0.196, 0.057, and 0.046, all P < 0.05). The C 0h of apixaban showed a moderate correlation with prothrombin time (r = 0.594 P < 0.001). Conclusion:The PXR*1B haplotype and POR*28 genotype statuses, which involve genes that impact the expression of multiple drug-metabolizing enzymes and drug-transporters, may affect the C 0h of apixaban.

Association between genotypes ofABCB1, ABCG2andCYP3A5and the risk of atrial fibrillation

“…28 Furthermore, recent studies have emphasized that the pharmacogenetic implications of these findings could connote the efficacy of direct oral anticoagulants (DOACs) being enhanced, as genetic variants influence drug metabolism and response. 29,30 In recent years, DOACs such as apixaban, dabigatran, edoxaban and rivaroxaban have replaced vitamin K antagonists for treating AF due to their ease of use and better effectiveness. In a rat model of pharmacokinetic interaction, almonertinib significantly increased systemic exposure to apixaban and rivaroxaban by inhibiting ABCB1 and ABCG2.…”