The interaction and transport of beta-lactam antibiotics with the cloned rat renal organic anion transporter 1.
In the present study, we investigated the interactions between antibiotics, especially beta-lactam antibiotics, and rat renal organic anion transporter 1 (OAT1). [(14)C]p-Aminohippurate (PAH) uptake via OAT1 expressed in Xenopus laevis oocytes was inhibited by all of the penicillins and cephalosporins tested. Penicillin G, carbenicillin, cephaloridine, cephalothin, cefazolin, and cephalexin inhibited [(14)C]PAH uptake via OAT1 in a competitive manner (K(i) = 0.29-2.33 mM). Cinoxacin, a quinolone gyrase inhibitor, also inhibited PAH uptake via OAT1. Other antibiotics, such as gentamicin, streptomycin, and vancomycin, which do not contain anionic moieties, did not interact with OAT1. [(3)H]Penicillin G and [(14)C]cephaloridine were demonstrated to be transported via OAT1. Using the cells that stably expressed OAT1, we analyzed the cytotoxicity of several beta-lactam antibiotics. Cells expressing OAT1 showed higher susceptibility to cephaloridine (a potentially nephrotoxic beta-lactam antibiotic) toxicity than did control cells. The present study suggests that OAT1 is the major organic anion transporter in the kidney that is responsible for the renal secretion of antibiotics, especially that of beta-lactam antibiotics. Furthermore, the culture cell system expressing OAT1 was revealed to be useful for the prediction of the nephrotoxicity of beta-lactam antibiotics.
Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Mitaka, Tokyo, Japan.
S
S
Jariyawat
T
T
Sekine
M
M
Takeda
N
N
Apiwattanakul
Y
Y
Kanai
S
S
Sophasan
H
H
Endou
D000818:Animals; D027321:Anion Transport Proteins; D000900:Anti-Bacterial Agents / Q000378:metabolism* / Q000494:pharmacology; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002509:Cephaloridine / Q000378:metabolism; D002511:Cephalosporins / Q000378:metabolism; D066298:In Vitro Techniques; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D009865:Oocytes; D010400:Penicillin G / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D014982:Xenopus laevis; D010130:p-Aminohippuric Acid / Q000378:metabolism*
D027321:Anion Transport Proteins; D000900:Anti-Bacterial Agents; D002352:Carrier Proteins; D002511:Cephalosporins; D011994:Recombinant Proteins; D002509:Cephaloridine; D010400:Penicillin G; D010130:p-Aminohippuric Acid