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Title: Interaction of human and rat organic anion transporter 2 with various cephalosporin antibiotics
Authors: Suparat Khamdang
Michio Takeda
Ellappan Babu
Rie Noshiro
Maristela Lika Onozato
Akihiro Tojo
Atsushi Enomoto
Xiu Lin Huang
Shinichi Narikawa
Naohiko Anzai
Pawinee Piyachaturawat
Hitoshi Endou
Kyorin University School of Medicine
Mahidol University
University of Tokyo
Fuji Biomedix Co Ltd
Keywords: Pharmacology, Toxicology and Pharmaceutics
Issue Date: 28-Mar-2003
Citation: European Journal of Pharmacology. Vol.465, No.1-2 (2003), 1-7
Abstract: Cephalosporin antibiotics are thought to be excreted into the urine via organic anion transporters (OATs) and OAT can mediate nephrotoxicity by cephalosporins, particularly by cephaloridine. The purpose of this study was to elucidate the interaction of human-OAT2 and rat-OAT2 with cephalosporin antibiotics using proximal tubule cells stably expressing human-OAT2 and rat-OAT2. Human-OAT2 is localized to the basolateral side of the proximal tubule, whereas rat-OAT2 is localized to the apical side of the proximal tubule. Cephalosporins tested were cephalothin, cefoperazone, cefazolin, ceftriaxone, cephaloridine, cefotaxime, cefadroxil and cefamandole. These cephalosporins dose-dependently inhibited organic anion uptake mediated by human-OAT2 and rat-OAT2. There was no species difference observed for the effects of OAT2 with cephalosporins between human and rat transporters. Kinetic analysis revealed that the inhibitory effects for human-OAT2 were competitive. Cephaloridine significantly decreased the viability of cells stably expressing human-OAT2, human-OAT1, human-OAT3 and human-OAT4. The decreased viability of cells stably expressing human-OAT1, human-OAT3 and human-OAT4 but not human-OAT2 was reversed by probenecid. In conclusion, human-OAT2 interacts with cephalosporins, and thus, human-OAT2 may mediate the uptake of cephalosporins on the basolateral side of the proximal tubule. The interaction of human-OAT2 with cephalosporins was the weakest among the basolateral human-OATs tested. In addition, it is suggested that human-OATs mediate cephaloridine-induced nephrotoxicity. © 2003 Elsevier Science B.V. All rights reserved.
ISSN: 00142999
Appears in Collections:Scopus 2001-2005

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