Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.
State Key Laboratory of Functions and Applications of Medicinal Plants, Key Laboratory of Pharmaceutics of Guizhou Province, Guizhou Medical University, Guiyang 550025, China.
Molecules. 2023 Feb 20;28(4):1995. doi: 10.3390/molecules28041995.
Bentysrepinine (Y101) is a novel phenylalanine dipeptide for the treatment of hepatitis B virus. Renal excretion played an important role in the elimination of Y101 and its metabolites, M8 and M9, in healthy Chinese subjects, although the molecular mechanisms of renal excretion and potential drug-drug interactions (DDIs) remain unclear. The present study aimed to determine the organic anion transporters (OATs) involved in the renal disposition of Y101 and to predict the potential DDI between Y101 and entecavir, the first-line agent against HBV and a substrate of OAT1/3. Pharmacokinetic studies and uptake assays using rat kidney slices, as well as hOAT1/3-HEK293 cells, were performed to evaluate potential DDI. The co-administration of probenecid (an inhibitor of OATs) significantly increased the plasma concentrations and area under the plasma concentration-time curves of M8 and M9 but not Y101, while reduced renal clearance and the cumulative urinary excretion of M8 were observed in rats. The time course of Y101 and M8 uptake via rat kidney slices was temperature-dependent. Moreover, the uptake of M8 was inhibited significantly by probenecid and benzylpenicillin, but not by -aminohippurate or tetraethyl ammonium. M8 was found to be a substrate of hOAT3, but Y101 is not a substrate of either hOAT1 or hOAT3. Additionally, the entecavir inhibited the uptake of M8 in the hOAT3-transfected cells and rat kidney slices in vitro. Interestingly, no significant changes were observed in the pharmacokinetic parameters of Y101, M8 or entecavir, regardless of intravenous or oral co-administration of Y101 and entecavir in rats. In conclusion, M8 is a substrate of OAT3 in rats and humans. Furthermore, M8 also mediates the DDI between Y101 and entecavir in vitro, mediated by OAT3. We speculate that it would be safe to use Y101 with entecavir in clinical practice. Our results provide useful information with which to predict the DDIs between Y101 and other drugs that act as substrates of OAT3.
苯丙氨酸二肽 Y101 是一种新型的治疗乙型肝炎病毒的药物。在健康的中国受试者中，肾脏排泄在 Y101 及其代谢物 M8 和 M9 的消除中起着重要作用，尽管肾脏排泄的分子机制和潜在的药物相互作用 (DDI) 仍不清楚。本研究旨在确定参与 Y101 肾脏处置的有机阴离子转运体 (OAT)，并预测 Y101 与恩替卡韦（HBV 的一线药物，也是 OAT1/3 的底物）之间的潜在 DDI。通过大鼠肾切片和 hOAT1/3-HEK293 细胞进行药代动力学研究和摄取实验，以评估潜在的 DDI。同时给予丙磺舒（OAT 抑制剂）可显著增加 M8 和 M9 的血药浓度和血药浓度-时间曲线下面积，但 Y101 没有变化，同时在大鼠中观察到肾清除率和 M8 的累积尿排泄减少。Y101 和 M8 通过大鼠肾切片的摄取随时间推移呈温度依赖性。此外，M8 的摄取被丙磺舒和苄青霉素显著抑制，但 -氨基马尿酸盐或四乙铵则没有。M8 被发现是 hOAT3 的底物，但 Y101 不是 hOAT1 或 hOAT3 的底物。此外，恩替卡韦在体外抑制 hOAT3 转染细胞和大鼠肾切片中 M8 的摄取。有趣的是，无论 Y101 和恩替卡韦静脉或口服联合给药，Y101、M8 或恩替卡韦的药代动力学参数均无显著变化。总之，M8 是大鼠和人类 OAT3 的底物。此外，M8 还介导了 Y101 和恩替卡韦在体外的 DDI，这是由 OAT3 介导的。我们推测，在临床实践中，Y101 与恩替卡韦联合使用是安全的。我们的研究结果为预测 Y101 与其他作为 OAT3 底物的药物之间的 DDI 提供了有用的信息。
