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Cilastatin protects against imipenem-induced nephrotoxicity via inhibition of renal organic anion transporters (OATs).

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.

SUBMITTER: Huo X

PROVIDER: S-EPMC6804466 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Cilastatin protects against imipenem-induced nephrotoxicity <i>via</i> inhibition of renal organic anion transporters (OATs).

Huo Xiaokui X Meng Qiang Q Wang Changyuan C Zhu Yanna Y Liu Zhihao Z Ma Xiaodong X Ma Xiaochi X Peng Jinyong J Sun Huijun H Liu Kexin K

Acta pharmaceutica Sinica. B 20190218 5

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 <i>in vitro</i> and in rabbits. Our results indicated that imipenem and cilastatin were substrates of hOAT1 and hOAT3. Cilastatin inhibit ...[more]

PMID: 31649848

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Project description:Nephrotoxicity induced by antimicrobial or anticancer drugs is a serious clinical problem. Megalin, an endocytic receptor expressed at the apical membranes of proximal tubules, mediates the nephrotoxicity of aminoglycosides and colistin, key antimicrobials for multidrug-resistant organisms. The mechanisms underlying the nephrotoxicity induced by vancomycin, an antimicrobial for methicillin-resistant Staphylococcus aureus, and cisplatin, an important anticancer drug, are unknown, although the nephrotoxicity of these drugs and gentamicin, an aminoglycoside, is suppressed experimentally with cilastatin. In the clinical setting, cilastatin has been used safely to suppress dehydropeptidase-I-mediated renal metabolism of imipenem, a carbapenem antimicrobial, and thereby limit tubular injury. Here, we tested the hypothesis that cilastatin also blocks megalin-mediated uptake of vancomycin, cisplatin, colistin, and aminoglycosides, thereby limiting the nephrotoxicity of these drugs. Quartz crystal microbalance analysis showed that megalin also binds vancomycin and cisplatin and that cilastatin competes with megalin for binding to gentamicin, colistin, vancomycin, and cisplatin. In kidney-specific mosaic megalin knockout mice treated with colistin, vancomycin, or cisplatin, the megalin-replete proximal tubule epithelial cells exhibited signs of injury, whereas the megalin-deficient cells did not. Furthermore, concomitant cilastatin administration suppressed colistin-induced nephrotoxicity in C57BL/6J mice. Notably, cilastatin did not inhibit the antibacterial activity of gentamicin, colistin, or vancomycin in vitro, just as cilastatin did not affect the anticancer activity of cisplatin in previous studies. In conclusion, megalin blockade with cilastatin efficiently suppresses the nephrotoxicity induced by gentamicin, colistin, vancomycin, or cisplatin. Cilastatin may be a promising agent for inhibiting various forms of drug-induced nephrotoxicity mediated via megalin in the clinical setting.

Dataset Information

Cilastatin protects against imipenem-induced nephrotoxicity via inhibition of renal organic anion transporters (OATs).

Publications

Cilastatin protects against imipenem-induced nephrotoxicity <i>via</i> inhibition of renal organic anion transporters (OATs).

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