Interaction of human organic anion transporters with various cephalosporin antibiotics.
Cephalosporin antibiotics are thought to be excreted into the urine via organic anion transporters (OATs). The purpose of this study was to elucidate the interaction of human-OATs with various cephalosporin antibiotics, using proximal tubule cells stably expressing human-OAT1, human-OAT3 and human-OAT4. Human-OAT1 and human-OAT3 are localized to the basolateral side of the proximal tubule, whereas human-OAT4 is localized to the apical side. The cephalosporin antibiotics tested were cephalothin, cefoperazone, cefazolin, ceftriaxone, cephaloridine, cefotaxime, cefadroxil and cefamandole. All of these cephalosporin antibiotics significantly inhibited organic anion uptake mediated by human-OAT1, human-OAT3 and human-OAT4. Kinetic analysis revealed that these inhibitions were competitive. The inhibition constant (K(i)) values of cefoperazone, cefazolin, ceftriaxone and cephaloridine for human-OAT1 were much lower than those for human-OAT3 and human-OAT4, whereas the K(i) values of cephalothin and cefotaxime for human-OAT3 were much lower than those for human-OAT1 and human-OAT4. Human-OAT4 mediated the bidirectional transport of estrone sulfate, an optimal substrate for human-OAT4. These results suggest that human-OAT1, human-OAT3 and human-OAT4 interact with various cephalosporin antibiotics, and that human-OAT1 and human-OAT3 play a distinct role in the basolateral uptake of cephalosporin antibiotics. Since the K(i) value of cephaloridine for human-OAT4-mediated organic uptake was much higher than that for human-OAT1, the results indicate the possibility that human-OAT4 limits the efflux of cephaloridine, leading to the accumulation of cephaloridine and the induction of nephrotoxicity.
Takeda
Michio
M
Department of Pharmacology and Toxicology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Tokyo 181-8611, Mitaka-shi, Japan.
Babu
Ellappan
E
Narikawa
Shinichi
S
Endou
Hitoshi
H
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002434:Cefadroxil / Q000494:pharmacology; D002439:Cefotaxime / Q000494:pharmacology; D002443:Ceftriaxone / Q000494:pharmacology; D002460:Cell Line; D002509:Cephaloridine / Q000494:pharmacology; D002511:Cephalosporins / Q000494:pharmacology*; D002512:Cephalothin / Q000494:pharmacology; D004970:Estrone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006801:Humans; D007700:Kinetics; D027381:Liver-Specific Organic Anion Transporter 1; D051379:Mice; D008822:Mice, Transgenic; D027362:Organic Anion Transport Protein 1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D027361:Organic Anion Transporters / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D029362:Organic Anion Transporters, Sodium-Independent / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D014316:Tritium
D002511:Cephalosporins; D027381:Liver-Specific Organic Anion Transporter 1; D027362:Organic Anion Transport Protein 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; C498886:SLC22A9 protein, human; C498887:Slco1b2 protein, mouse; C114338:organic anion transport protein 3; D014316:Tritium; D002434:Cefadroxil; D004970:Estrone; D002443:Ceftriaxone; D002509:Cephaloridine; D002439:Cefotaxime; C017296:estrone sulfate; D002512:Cephalothin