西司他丁通过与双氯芬酸酰基葡萄糖醛酸经有机阴离子转运体相互作用对双氯芬酸诱导的肾毒性的保护作用。
Protective effect of cilastatin against diclofenac-induced nephrotoxicity through interaction with diclofenac acyl glucuronide via organic anion transporters.
作者信息
Huo Xiaokui, Meng Qiang, Wang Changyuan, Wu Jingjing, Wang Chong, Zhu Yanna, Ma Xiaodong, Sun Huijun, Liu Kexin
机构信息
Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.
College (Institute) of Integrative Medicine, Dalian Medical University, Dalian, China.
出版信息
Br J Pharmacol. 2020 May;177(9):1933-1948. doi: 10.1111/bph.14957. Epub 2020 Mar 5.
BACKGROUND AND PURPOSE
Diclofenac is a widely used nonsteroidal anti-inflammatory drug. However, adverse effects in the kidney limit its clinical application. The present study was aimed to evaluate the potential effect of cilastatin on diclofenac-induced acute kidney injury and to clarify the potential roles of renal organic anion transporters (OATs) in the drug-drug interaction between cilastatin and diclofenac.
EXPERIMENTAL APPROACH
The effect of cilastatin was evaluated in diclofenac-induced acute kidney injury in mice. Human OAT1/3-transfected HEK293 cells and renal primary proximal tubule cells (RPTCs) were used to investigate OAT1/3-mediated transport and the cytotoxicity of diclofenac.
KEY RESULTS
Cilastatin treatment decreased the pathological changes, renal dysfunction and elevated renal levels of oxidation products, cytokine production and apoptosis induced by diclofenac in mice. Moreover, cilastatin increased the plasma concentration and decreased the renal distribution of diclofenac and its glucuronide metabolite, diclofenac acyl glucuronide (DLF-AG). Similarly, cilastatin inhibited cytotoxicity and mitochondrial damage in RPTCs but did not change the intracellular accumulation of diclofenac. DLF-AG but not diclofenac exhibited OAT-dependent cytotoxicity and was identified as an OAT1/3 substrate. Cilastatin inhibited the intracellular accumulation and decreased the cytotoxicity of DLF-AG in RPTCs.
CONCLUSION AND IMPLICATIONS
Cilastatin alleviated diclofenac-induced acute kidney injury in mice by restoring the redox balance, suppressing inflammation, and reducing apoptosis. Cilastatin inhibited OATs and decreased the renal distribution of diclofenac and DLF-AG, which further ameliorated the diclofenac-induced nephrotoxicity in mice. Cilastatin can be potentially used in the clinic as a therapeutic agent to alleviate the adverse renal reaction to diclofenac.
背景与目的
双氯芬酸是一种广泛使用的非甾体抗炎药。然而，其对肾脏的不良反应限制了它的临床应用。本研究旨在评估西司他丁对双氯芬酸诱导的急性肾损伤的潜在作用，并阐明肾脏有机阴离子转运体（OATs）在西司他丁与双氯芬酸药物相互作用中的潜在作用。
实验方法
在双氯芬酸诱导的小鼠急性肾损伤中评估西司他丁的作用。使用人OAT1/3转染的HEK293细胞和肾原代近端小管细胞（RPTCs）研究OAT1/3介导的转运以及双氯芬酸的细胞毒性。
主要结果
西司他丁治疗减轻了双氯芬酸诱导的小鼠病理变化、肾功能障碍以及氧化产物、细胞因子生成和凋亡的肾脏水平升高。此外，西司他丁增加了双氯芬酸及其葡糖醛酸代谢物双氯芬酸酰基葡糖醛酸（DLF-AG）的血浆浓度并降低了其在肾脏中的分布。同样，西司他丁抑制了RPTCs中的细胞毒性和线粒体损伤，但未改变双氯芬酸的细胞内蓄积。DLF-AG而非双氯芬酸表现出OAT依赖性细胞毒性，并被鉴定为OAT1/3底物。西司他丁抑制了RPTCs中DLF-AG的细胞内蓄积并降低了其细胞毒性。
结论与意义
西司他丁通过恢复氧化还原平衡、抑制炎症和减少凋亡减轻了双氯芬酸诱导的小鼠急性肾损伤。西司他丁抑制OATs并降低了双氯芬酸和DLF-AG在肾脏中的分布，这进一步改善了双氯芬酸诱导的小鼠肾毒性。西司他丁有可能在临床上用作治疗剂，以减轻对双氯芬酸的不良肾脏反应。
Zotero 插件