Little is known about the influence of non-synonymous genetic variations in the organic anion-transporting polypeptide (OATP) 1A2 on the transport kinetics of its substrate fexofenadine. Moreover, the pH-dependency of fexofenadine uptake also remains unclear. This study aimed to evaluate the effects of genetic variants (Ile13Thr, Asn128Tyr, Glu172Asp, Ala187Thr, and Thr668Ser) on the OATP1A2-mediated uptake of fexofenadine at pH 6.3 and 7.4 and compare the pH dependency of OATP1A2-mediated uptake of fexofenadine and estrone 3-sulfate. The uptake clearances of 0.3 μM and 300 μM fexofenadine were compared with those of 0.3 μM and 300 μM estrone 3-sulfate at pH 6.3 and 7.4. Among the six variants examined, the Thr668Ser variant showed the highest fexofenadine uptake clearance (V_max/K_m); i.e., 4.53- and 6.28-fold higher uptake clearance than the wild type at pH 6.3 and 7.4, respectively. All variants exhibited significantly higher fexofenadine uptake at pH 6.3 than at pH 7.4. Compared with estrone 3-sulfate uptake, the uptake of 0.3 μM fexofenadine was less sensitive to pH. Our findings suggest that genetic variations in OATP1A2 may lead to altered intestinal absorption of fexofenadine, such as increased absorption in subjects bearing the Thr668Ser variant, which showed higher uptake activity.

关于有机阴离子转运多肽 (OATP) 1A2 中的非同义遗传变异对其底物非索非那定的转运动力学的影响知之甚少。此外，非索非那定摄取的 pH 依赖性也仍不清楚。本研究旨在评估遗传变异（Ile13Thr、Asn128Tyr、Glu172Asp、Ala187Thr 和 Thr668Ser）在 pH 6.3 和 7.4 下对 OATP1A2 介导的非索非那定摄取的影响，并比较 OATP1A2 介导的非索非那定和雌酮摄取的 pH 依赖性 3 -硫酸盐。在 pH 6.3 和 7.4 下，将 0.3 μM 和 300 μM 非索非那定的摄取清除率与 0.3 μM 和 300 μM 雌酮 3-硫酸盐的摄取清除率进行了比较。在检查的六个变体中，Thr668Ser 变体显示出最高的非索非那定摄取清除率₍ Vmax / K_米）；即，在 pH 6.3 和 7.4 下，摄取清除率分别比野生型高 4.53 倍和 6.28 倍。所有变体在 pH 6.3 时表现出比在 pH 7.4 时显着更高的非索非那定摄取。与雌酮 3-硫酸盐摄取相比，0.3 μM 非索非那定的摄取对 pH 不太敏感。我们的研究结果表明，OATP1A2 的遗传变异可能导致非索非那定的肠道吸收改变，例如携带 Thr668Ser 变体的受试者吸收增加，这显示出更高的摄取活性。