Protective effect of cilastatin against diclofenac‐induced nephrotoxicity through interaction with diclofenac acyl glucuronide via organic anion transporters

Abstract

Background and Purpose: Diclofenac is a widely used nonsteroidal antiinflammatory 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 OATdependent 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.

Bone Marrow-Derived Mesenchymal Stem Cells Ameliorate Sepsis-Induced Acute Kidney Injury by Promoting Mitophagy of Renal Tubular Epithelial Cells via the SIRT1/Parkin Axis

“…Oxidative stress-mediated apoptosis of kidney tubular cells is recognized as a fundamental mechanism in kidney injury (29). Huo et al have shown that inhibiting apoptosis and reducing inflammation may ameliorate diclofenac-induced AKI in mice (46). We exhibited that BMSCs inhibited RTEC apoptosis in rats with SI-AKI.…”

The Role of Uptake and Efflux Transporters in the Disposition of Glucuronide and Sulfate Conjugates

“…OAT1 and OAT3 transport some glucuronide and sulfate conjugates of endogenous compounds and xenobiotics, but only a small number of drug conjugates have been identified as their substrates ( Table 1 , Supplementary Table S1 ). Morinidazole-S, edaravone-S and diclofenac-AG are transported by both OAT1 and OAT3 ( Mizuno et al, 2007a ; Zhong et al, 2014 ; Zhang et al, 2016 ; Huo et al, 2020 ). On the other hand, OAT3, but not OAT1, transports ethinylestradiol-S and glucuronides such as of cabotegravir-G, curcumin-G, genistein-7-G, steviol-G and MPA-G ( Uwai et al, 2007 ; Han et al, 2010a ; Wong et al, 2011b ; Wang M. et al, 2015 ; Zhou et al, 2017 ; Patel et al, 2019 ).…”

Targeting renal OATs to develop renal protective agent from traditional Chinese medicines: Protective effect of Apigenin against Imipenem‐induced nephrotoxicity

“…Rabbit primary proximal tubule cells were isolated from male rabbits by the previous method with minor modifications (Huo et al, 2020). Briefly, rabbits were anesthetized with diethyl ether, and kidneys were perfused with Ca 2+ free Hank's buffer (pH 7.4) containing 25 mmol/L HEPES (HBSS) to remove blood, and then kidneys were removed and minced in a sterile cell culture dish on ice.…”