Leflunomide increased the renal exposure of acyclovir by inhibiting OAT1/3 and MRP2.,Acta Pharmacologica Sinica

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Leflunomide increased the renal exposure of acyclovir by inhibiting OAT1/3 and MRP2.
Acta Pharmacologica Sinica ( IF 6.9 ) Pub Date : 2019-07-24 , DOI: 10.1038/s41401-019-0283-z
Xiao-Ying Liao ₁ , Qiang-Qiang Deng ₂ , Li Han _{2,

3} , Zhi-Tao Wu ₂ , Zhao-Liang Peng ₂ , Yuan Xie ₁ , Guang-Ji Wang ₁ , Ji-Ye Aa ₁ , Guo-Yu Pan _{2,

3}

Affiliation

Rheumatoid arthritis patients can be prescribed a combination of immunosuppressive drug leflunomide (LEF) and the antiviral drug acyclovir to reduce the high risk of infection. Acyclovir is a substrate of organic anion transporter (OAT) 1/3 and multidrug resistance-associated protein (MRP) 2. Considering the extraordinarily long half-life of LEF's active metabolite teriflunomide (TER) and the kidney injury risk of acyclovir, it is necessary to elucidate the potential impact of LEF on the disposition of acyclovir. Here we used a specific MRP inhibitor MK571 and probenecid (OAT1/3 and MRP2 inhibitor) to assess the effects of MRP2 and OAT1/3 on the pharmacokinetics and tissue distribution of acyclovir in rats. We showed that LEF and probenecid, but not MK571 significantly increased the plasma concentration of acyclovir. However, kidney and liver exposures of acyclovir were increased when coadministered with LEF, probenecid or MK571. The kidney/plasma ratio of acyclovir was increased to approximately 2-fold by LEF or probenecid, whereas it was increased to as much as 14.5-fold by MK571. Consistently, these drugs markedly decreased the urinary excretion of acyclovir. TER (0.5-100 μmol/L) dose-dependently increased the accumulation of acyclovir in MRP2-MDCK cells with an IC50 value of 4.91 μmol/L. TER (5 μmol/L) significantly inhibited the uptake of acyclovir in hOAT1/3-HEK293 cells. These results suggest that LEF/TER increased the kidney accumulation of acyclovir by inhibiting the efflux transporter MRP2, which increased its kidney/plasma ratio and renal injury risk. However, the inhibitory effects of LEF/TER on OAT1/3 reduced the tubular cells' uptake of acyclovir and increased the plasma concentration.

中文翻译：

来氟米特通过抑制 OAT1/3 和 MRP2 增加阿昔洛韦的肾脏暴露。

类风湿关节炎患者可以服用免疫抑制药物来氟米特 (LEF) 和抗病毒药物阿昔洛韦的组合，以降低感染的高风险。阿昔洛韦是有机阴离子转运蛋白 (OAT) 1/3 和多药耐药相关蛋白 (MRP) 2 的底物。考虑到 LEF 的活性代谢物特立氟胺 (TER) 的超长半衰期和阿昔洛韦的肾损伤风险，它是有必要阐明 LEF 对阿昔洛韦处置的潜在影响。在这里，我们使用特定的 MRP 抑制剂 MK571 和丙磺舒（OAT1/3 和 MRP2 抑制剂）来评估 MRP2 和 OAT1/3 对阿昔洛韦在大鼠体内的药代动力学和组织分布的影响。我们发现 LEF 和丙磺舒，但不是 MK571 显着增加了阿昔洛韦的血浆浓度。然而，当与 LEF、丙磺舒或 MK571 共同给药时，阿昔洛韦的肾脏和肝脏暴露量增加。LEF 或丙磺舒将阿昔洛韦的肾脏/血浆比率增加到大约 2 倍，而 MK571 将其增加到多达 14.5 倍。一致地，这些药物显着降低了阿昔洛韦的尿排泄。TER (0.5-100 μmol/L) 剂量依赖性地增加阿昔洛韦在 MRP2-MDCK 细胞中的积累，IC50 值为 4.91 μmol/L。TER (5 μmol/L) 显着抑制 hOAT1/3-HEK293 细胞中阿昔洛韦的摄取。这些结果表明，LEF/TER 通过抑制外排转运蛋白 MRP2 增加了阿昔洛韦的肾脏积累，从而增加了其肾脏/血浆比率和肾损伤风险。然而，LEF/TER 对 OAT1/3 的抑制作用降低了肾小管细胞的

更新日期：2019-11-18

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