Clinical Pharmacy Research Group, Louvain Drug Research Institute, Université catholique de Louvain (UCL), Brussels, Belgium.
Department of Pharmacy, Namur Research Institute for LIfe Sciences, Namur Thrombosis and Hemostasis Center (NTHC), University of Namur, Namur, Belgium.
Sci Rep. 2018 Jul 12;8(1):10514. doi: 10.1038/s41598-018-28622-4.
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.
直接口服抗凝剂（DOAC）是 ABCB1 转运体（也称为 P-糖蛋白）的底物，是一种主动外排泵。先前已经报道了 ABCB1 多态性会影响几种药物的药代动力学，如免疫抑制剂和酪氨酸激酶抑制剂。最近，体内研究表明，遗传变异可能导致 DOAC 血浆浓度的个体间变异性。因此，我们评估了最常见的编码 ABCB1 单核苷酸多态性（SNP）1236C > T-2677G > T-3435C > T 和编码 ABCB1 1199G > A SNP 对 rivaroxaban 转运活性的体外影响。HEK293 细胞转染以过表达 ABCB1 野生型（1236C-2677G-3435C、1199G）或变体蛋白（1236C-2677G-3435T、1236T-2677T-3435T 或 1199A）。与对照细胞相比，ABCB1 表达降低了 rivaroxaban 的细胞内积累。这证实了 ABCB1 参与了 rivaroxaban 的主动转运。然而，与野生型蛋白相比，ABCB1 1236C > T-2677G > T-3435C > T 和 1199G > A SNP 对 rivaroxaban 的细胞内积累没有显著影响。这些结果表明，本研究中研究的 ABCB1 编码 SNP 不太可能导致 rivaroxaban 血浆浓度的个体间变异性。
