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 transporte r 1 (OAT1). [C-14]p-Aminohippurate (PAH) uptake via OAT1 expressed in Xenop us laevis oocytes was inhibited by all of the penicillins and cephalosporin s tested. Penicillin G, carbenicillin, cephaloridine, cephalothin, cefazoli n, and cephalexin inhibited [C-14]PAH uptake via OAT1 in a competitive mann er (K-i = 0.29-2.33 mM). Cinoxacin, a quinolone gyrase inhibitor, also inhi bited PAH uptake via OAT1. Other antibiotics, such as gentamicin, streptomy cin, and vancomycin, which do not contain anionic moieties, did not interac t with OAT1. [H-3]Penicillin G and [(14)G]cephaloridine were demonstrated t o be transported via OAT1. Using the cells that stably expressed OAT1, we a nalyzed the cytotoxicity of several beta-lactam antibiotics. Cells expressi ng OAT1 showed higher susceptibility to cephaloridine (a potentially nephro toxic beta-lactam antibiotic) toxicity than did control cells. The present study suggests that OAT1 is the major organic anion transporter in the kidn ey that is responsible for the renal secretion of antibiotics, especially t hat of beta-lactam antibiotics. Furthermore, the culture cell system expres sing OAT1 was revealed to be useful for the prediction of the nephrotoxicit y of beta-lactam antibiotics.