ABCB1 and CYP3A5 gene polymorphisms significantly impacted rivaroxaban plasma levels, with heterozygous ABCB1 and homozygous CYP3A5 variants experiencing more bleeding events.
Cohort (n=66)
Do ABCB1 and CYP3A5 gene polymorphisms affect rivaroxaban plasma levels and bleeding events in naive patients with nonvalvular atrial fibrillation?
Polymorphisms in ABCB1 and CYP3A5 genes significantly alter rivaroxaban plasma levels and are associated with increased bleeding risk in patients with nonvalvular atrial fibrillation.
Background and Objectives: Rivaroxaban is a direct-acting anticoagulant used to prevent stroke in patients with atrial fibrillation. Rivaroxaban is a substrate for P-glycoprotein, which is encoded by the ABCB1 gene. Rivaroxaban is also metabolized by the CYP3A5 gene. Therefore, the current study is carried out to study the effects of polymorphisms in the ABCB1 and CYP3A5 genes, which may affect the plasma levels of rivaroxaban, with subsequent clinical outcomes (bleeding events) associated with the therapy. Materials and Methods: The study was conducted on 66 naive patients with atrial fibrillation treated with rivaroxaban. Blood samples of rivaroxaban were taken at 3 h and after 1 month following the administration of the drug to measure plasma levels. The blood level of rivaroxaban was measured with an HPLC-UV detector. Sanger sequencing was used to find polymorphisms in the targeted genes. Coagulation parameters were measured at 3 h and after 1 month of administration of rivaroxaban. Frequencies of bleeding events were recorded throughout the one-month course of drug therapy. Results: The heterozygous and homozygous mutant genotypes of ABCB1 (rs2032582, rs1045642, rs1128503, and rs4148738) and CYP3A5 (rs776746) showed lower plasma concentrations as compared to the wild-type genotype. ABCB1 (rs2032582, rs1045642, rs1128503, and rs4148738) and CYP3A5 (rs776746) gene polymorphisms had a statistically significant impact on the plasma concentration of rivaroxaban among the heterozygous and homozygous mutant genotypes compared to the wild-type genotype. The heterozygous variant of ABCB1 and homozygous variant of CYP3A5 suffered more events of bleeding. Conclusions: It was concluded that ABCB1 (rs2032582, rs1045642, rs1128503, and rs4148738) and CYP3A5 (rs776746) gene polymorphisms had a significant impact on the plasma levels of rivaroxaban in patients treated for atrial fibrillation on day three as well as after one month of the therapy. The lowest plasma levels were observed in patients with a homozygous variant of ABCB1 (rs2032582, rs1045642, or rs4148738) along with the CYP3A5*1/*3 allele. The heterozygous variant of ABCB1 SNPs and homozygous variant of CYP3A5 SNPs suffered more events of bleeding.
Ain et al. (2024) conducted a cohort in Nonvalvular Atrial Fibrillation (n=66). Rivaroxaban vs. Wild-type genotype (ABCB1 and CYP3A5) was evaluated on Plasma concentration of rivaroxaban and bleeding events. ABCB1 and CYP3A5 gene polymorphisms significantly impacted rivaroxaban plasma levels, with heterozygous ABCB1 and homozygous CYP3A5 variants experiencing more bleeding events.