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

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 fibrillation (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.