Interaction of human and rat organic anion transporter 2 with various cephalosporin antibiotics.
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.
Khamdang
Suparat
S
Department of Pharmacology and Toxicology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka Tokyo 181, Japan.
Takeda
Michio
M
Babu
Ellappan
E
Noshiro
Rie
R
Onozato
Maristela Lika
ML
Tojo
Akihiro
A
Enomoto
Atsushi
A
Huang
Xiu-Lin
XL
Narikawa
Shinichi
S
Anzai
Naohiko
N
Piyachaturawat
Pawinee
P
Endou
Hitoshi
H
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002434:Cefadroxil / Q000494:pharmacology; D002435:Cefamandole / Q000494:pharmacology; D002437:Cefazolin / Q000494:pharmacology; D002438:Cefoperazone / Q000494:pharmacology; D002439:Cefotaxime / Q000494:pharmacology; D002443:Ceftriaxone / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002509:Cephaloridine / Q000494:pharmacology; D002511:Cephalosporins / Q000494:pharmacology*; D002512:Cephalothin / Q000494:pharmacology; D015237:Dinoprost / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D051379:Mice; D008822:Mice, Transgenic; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism*; D011339:Probenecid / Q000494:pharmacology; D051381:Rats; D014162:Transfection; D014528:Uricosuric Agents / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D029362:Organic Anion Transporters, Sodium-Independent; C490280:SLC22A7 protein, human; C490281:Slc22a7 protein, mouse; C088800:Slc22a7 protein, rat; D014528:Uricosuric Agents; D002434:Cefadroxil; D002435:Cefamandole; D002443:Ceftriaxone; D002438:Cefoperazone; D015237:Dinoprost; D002437:Cefazolin; D002509:Cephaloridine; D002439:Cefotaxime; D011339:Probenecid; D002512:Cephalothin