Wang Chong, Wang Changyuan, Wu Jingjing, Meng Qiang, Jin Huan, Sun Huijun, Kaku Taiichi, Chen Jing, Huo Xiaokui, Liu Kexin
Institute of Integrative Medicine, Dalian Medical University, Dalian, China.
Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.
Front Pharmacol. 2022 Jun 8;13:938813. doi: 10.3389/fphar.2022.938813. eCollection 2022.
Imipenem (IMP) possesses a broad spectrum of antibacterial activity; however, nephrotoxicity limits its clinical application in patients with renal insufficiency. In our previous studies, a dipeptide, JBP485, a dipeptide with the chemical structure cyclo-trans-4-L-hydroxyprolyl-L-serine, was found to attenuate drug-induced kidney injury. The current study aimed to explore whether JBP485 could relieve IMP-induced kidney injury and clarify the potential molecular pharmacokinetic mechanism. The effects of JBP485 on IMP nephrotoxicity were evaluated in rabbits and human kidney 2 (HK-2) cells. Drug-drug interactions (DDIs) mediated by organic anion transporters (OATs) and dehydropeptidase-I (DHP-I) were explored through pharmacokinetic studies in rats, metabolism assays in the kidney, and uptake studies in OAT-over-expressing cells. The results revealed that JBP485 significantly ameliorated IMP-induced nephrotoxicity in rabbits. Further, incubation of HK-2 cells with JBP485 or cilastatin markedly improved the cell survival rate, inhibited apoptosis and attenuated mitochondrial damage by improving the stability of IMP and reducing its intracellular accumulation. This suggests that DHP-I and OATs might be involved in the protective effect of JBP485. Furthermore, coadministration with JBP485 significantly increased the IMP's plasma concentration as well as the area under the plasma concentration-time curve (AUC), while decreasing IMP renal clearance and cumulative urinary excretion. Moreover, JBP485 reduced IMP uptake in kidney slices and OAT1/3-human embryonic kidney 293 (HEK293) cells. At the same time, the metabolism of IMP by DHP-I was inhibited by JBP485 with an IC value of 12.15 ± 1.22 μM. Finally, the molecular docking assay revealed a direct interaction between JBP485 and OAT1/3 or DHP-I. In conclusion, JBP485 protected against IMP nephrotoxicity in rabbits and HK-2 cells by improving IMP stability and reducing its intracellular accumulation via simultaneous inhibition of renal OATs and DHP-I. JBP485 is a promising renoprotective agent and could serve as an effective supplement to reduce IMP-induced adverse renal reactions in the clinical setting.
亚胺培南（IMP）具有广泛的抗菌活性；然而，肾毒性限制了其在肾功能不全患者中的临床应用。在我们之前的研究中，发现一种二肽JBP485（化学结构为环反式-4-L-羟基脯氨酰-L-丝氨酸的二肽）可减轻药物诱导的肾损伤。本研究旨在探讨JBP485是否能减轻IMP诱导的肾损伤，并阐明其潜在的分子药代动力学机制。在兔和人肾2（HK-2）细胞中评估了JBP485对IMP肾毒性的影响。通过大鼠药代动力学研究、肾脏代谢分析以及在过表达OAT的细胞中的摄取研究，探讨了有机阴离子转运体（OATs）和脱氢肽酶-I（DHP-I）介导的药物-药物相互作用（DDIs）。结果显示，JBP485显著改善了IMP诱导的兔肾毒性。此外，用JBP485或西司他丁孵育HK-2细胞可显著提高细胞存活率、抑制细胞凋亡并通过提高IMP的稳定性和减少其细胞内蓄积减轻线粒体损伤。这表明DHP-I和OATs可能参与了JBP485的保护作用。此外，与JBP485合用显著提高了IMP的血浆浓度以及血浆浓度-时间曲线下面积（AUC），同时降低了IMP的肾脏清除率和累积尿排泄量。此外，JBP485降低了肾脏切片和OAT1/3-人胚肾293（HEK293）细胞对IMP的摄取。同时，JBP485以12.15±1.22μM的IC值抑制了DHP-I对IMP的代谢。最后，分子对接分析揭示了JBP485与OAT1/3或DHP-I之间的直接相互作用。总之，JBP485通过提高IMP稳定性并通过同时抑制肾脏OATs和DHP-I减少其细胞内蓄积，从而保护兔和HK-2细胞免受IMP肾毒性的影响。JBP485是一种有前景的肾脏保护剂，可作为一种有效的补充剂，以减少临床环境中IMP诱导的不良肾脏反应。
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