Cilastatin protects against imipenem-induced nephrotoxicity inhibition of renal organic anion transporters (OATs).
10.1016/j.apsb.2019.02.005
- Author:
Xiaokui HUO
1
;
Qiang MENG
1
;
Changyuan WANG
1
;
Yanna ZHU
1
;
Zhihao LIU
1
;
Xiaodong MA
1
;
Xiaochi MA
1
;
Jinyong PENG
1
;
Huijun SUN
1
;
Kexin LIU
1
Author Information
1. Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China.
- Publication Type:Journal Article
- Keywords:
BUN, blood urea nitrogen;
CKD, chronic kidney disease;
CLp, plasma clearance;
CLr, renal clearance;
CRE, creatinine;
Cil, cilastatin;
Cilastatin;
DDIs, drug-drug interactions;
DHP-I, renal dehydropeptidase-I;
ES, estrone-3-sulfate;
GSH, glutathione;
Imipenem;
Imp, imipenem;
MDA, malonaldehyde;
Nephrotoxicity;
OATs;
OATs, renal organic anion transporters;
PAH, p-aminophenol acid;
Prb, probenecid;
Probenecid;
SNP, single nucleotide polymorphism;
hOAT, human OAT;
hOAT1;
hOAT3;
rOAT, rat OAT;
rPTCs, rabbit primary proximal tubule cells;
raOAT, rabbit OAT;
t1/2, half life
- From:
Acta Pharmaceutica Sinica B
2019;9(5):986-996
- CountryChina
- Language:English
-
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 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 IC 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.
