Original articles
Xiaokui Huo, Qiang Meng, Changyuan Wang, Yanna Zhu, Zhihao Liu, Xiaodong Ma, Xiaochi Ma, Jinyong Peng, Huijun Sun, Kexin Liu. Cilastatin protects against imipenem-induced nephrotoxicity via inhibition of renal organic anion transporters (OATs)[J]. Acta Pharmaceutica Sinica B, 2019, 9(5): 986-996

Cilastatin protects against imipenem-induced nephrotoxicity via inhibition of renal organic anion transporters (OATs)
Xiaokui Huoa,b,c, Qiang Menga,b,c, Changyuan Wanga,b,c, Yanna Zhua, Zhihao Liua, Xiaodong Maa, Xiaochi Maa,b,c, Jinyong Penga,b,c, Huijun Suna,b,c, Kexin Liua,b,c
a Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China;
b College(Institute) of Integrative Medicine, Dalian Medical University, Dalian 116044, China;
c Provincial Key Laboratory for Pharmacokinetics and Transport, Dalian Medical University, Dalian 116044, China
Abstract:
Imipenem is a carbapenem antibiotic. However, Imipenem could not be marketed owing to its instability and nephrotoxicity until cilastatin, an inhibitor of renal dehydropeptidase-I (DHP-I), was developed. In present study, the potential roles of renal organic anion transporters (OATs) in alleviating the nephrotoxicity of imipenem by cilastatin were investigated in vitro and in rabbits. Our results indicated that imipenem and cilastatin were substrates of hOAT1 and hOAT3. Cilastatin inhibited hOAT1/3-mediated transport of imipenem with IC50 values comparable to the clinical concentration, suggesting the potential to cause a clinical drug-drug interaction (DDI). Moreover, imipenem exhibited hOAT1/3-dependent cytotoxicity, which was alleviated by cilastatin and probenecid. Furthermore, cilastatin and probenecid ameliorated imipenem-induced rabbit acute kidney injury, and reduced the renal secretion of imipenem. Cilastatin and probenecid inhibited intracellular accumulation of imipenem and sequentially decreased the nephrocyte toxicity in rabbit primary proximal tubule cells. Renal OATs, besides DHP-I, was also the target of interaction between imipenem and cilastatin, and contributed to the nephrotoxicity of imipenem. This therefore gives in part the explanation about the mechanism by which cilastatin protected against imipenem-induced nephrotoxicity. Thus, OATs can potentially be used as a therapeutic target to avoid the renal adverse reaction of imipenem in clinic.
Key words:    Imipenem    Cilastatin    Probenecid    OATs    hOAT1    hOAT3    Nephrotoxicity   
Received: 2018-11-02     Revised: 2018-11-29
DOI: 10.1016/j.apsb.2019.02.005
Funds: The work was supported by a grant from the National Natural Science Foundation of China, China (Nos. 81874324, 81473280, and U1608283) and Dalian Science and technology innovation found, China (No. 2018J12SN065). The authors thank Prof. Yuichi Sugiyama (Sugiyama Laboratory, RIKEN, Japan) for kindly providing Mock/hOAT1/3-HEK293 cells.
Corresponding author: Kexin Liu     Email:kexinliu@dlmedu.edu.cn
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Xiaokui Huo
Qiang Meng
Changyuan Wang
Yanna Zhu
Zhihao Liu
Xiaodong Ma
Xiaochi Ma
Jinyong Peng
Huijun Sun
Kexin Liu

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