Effect of ABCB1 genetic polymorphisms on the transport of rivaroxaban in HEK293 recombinant cell lines

Abstract

Direct oral anticoagulants (DOAC) are substrates for the ABCB1 transporter (also called P-glycoprotein), an active efflux pump. ABCB1 polymorphisms have been previously reported to influence the pharmacokinetics of several drugs such as immunosuppressants and tyrosine kinase inhibitors. Recently, in vivo studies have suggested that genetic variants might contribute to the inter-individual variability in DOAC plasma concentrations. Therefore, we evaluated the in vitro effect of the most common coding ABCB1 single nucleotide polymorphisms (SNP), 1236 C > T-2677G > T-3435C > T, and the coding ABCB1 1199 G > A SNP on the transport activity towards rivaroxaban. HEK293 cells were transfected to overexpress the ABCB1 wild-type (1236C-2677G-3435C, 1199 G) or variant proteins (1236C-2677G-3435T, 1236T-2677T-3435T or 1199 A). ABCB1 expression decreased the intracellular accumulation of rivaroxaban, when compared to control cells. This confirms the involvement of ABCB1 in the active transport of rivaroxaban. However, the ABCB1 1236 C > T-2677G > T-3435C > T and 1199 G > A SNPs had no significant influence on the intracellular accumulation of rivaroxaban when compared to the wild-type protein. These results suggest that the ABCB1 coding SNPs investigated in the present study are unlikely to contribute to the inter-individual variability in rivaroxaban plasma concentrations.

Developing Deep Venous Thrombosis while on Rivaroxaban: A Review of Rivaroxaban

“…These combined genetic changes led to the estimated half-life of rivaroxaban increasing by threefold in the reported patient [36]. However, this explanation was contradicted by the work done by Sennesael et al [37] who concluded that the ABCB1 1236 C > T-2677G > T-3435C > T and 1199 G > A SNPs had no significant influence on the intracellular accumulation of rivaroxaban when compared to the wild-type protein [37]. But, their work confirmed the role of ABCB1 in transporting the drug.…”

“…The ABCB1 gene is located on chromosome 7 and is composed of 29 exons in a 251.3-kb genomic region [36]. The three most common SNPs in the coding region are rs1128503 (1236 C>T, Gly412Gly), rs2032582 (2677 G>T, Ala893Ser) and rs1045642 (3435 C > T, Ile1145Ile) [37]. They are in strong linkage disequilibrium and present a minor allelic frequency around 50% in the Caucasian population [37].…”

“…The three most common SNPs in the coding region are rs1128503 (1236 C>T, Gly412Gly), rs2032582 (2677 G>T, Ala893Ser) and rs1045642 (3435 C > T, Ile1145Ile) [37]. They are in strong linkage disequilibrium and present a minor allelic frequency around 50% in the Caucasian population [37]. ABCB1 gene encodes the P-glycoprotein (P-gp), a 170 kDa transmembrane transporter, and exists in the xenobiotic barriers including the placenta, blood-brain barrier, and the blood-testis barrier, etc.…”

“…ABCB1 gene encodes the P-glycoprotein (P-gp), a 170 kDa transmembrane transporter, and exists in the xenobiotic barriers including the placenta, blood-brain barrier, and the blood-testis barrier, etc. [26,37] (Figure 2). As stated previously, the functionality of the P-gp depends on its histological location; presence in the hepatocyte enhances biliary excretion.…”

“…As stated previously, the functionality of the P-gp depends on its histological location; presence in the hepatocyte enhances biliary excretion. In the brush border of proximal tubule cells it enhances renal excretion while it presence in the apical membrane of enterocytes it limits absorption [37] ( Figure 2). rs2032582 (C.2677G>T) and rs1045642 (C.3435C>T) are among the 100 polymorphisms of ABCB1 that have been shown to affect rivaroxaban metabolism [18,36].…”