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Vol. 290, Issue 2, 672-677, August 1999
-Lactam Antibiotics with the
Cloned Rat Renal Organic Anion Transporter 11
Department of Pharmacology and Toxicology, Kyorin
University School of Medicine, Mitaka, Tokyo, Japan (S.J., T.S., M.T.,
N.A., Y.K., H.E.); and Department of Physiology, Faculty of Science,
Mahidol University, Bangkok, Thailand (S.J., N.A., S.S.)
In the present study, we investigated the interactions between
antibiotics, especially 
-lactam antibiotics, and rat renal organic
anion transporter 1 (OAT1).
[14C]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 [14C]PAH uptake via OAT1 in a competitive
manner (Ki = 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.
[3H]Penicillin G and [14C]cephaloridine
were demonstrated to be transported via OAT1. Using the cells that
stably expressed OAT1, we analyzed the cytotoxicity of several
-lactam antibiotics. Cells expressing OAT1 showed higher
susceptibility to cephaloridine (a potentially nephrotoxic -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
-lactam antibiotics. Furthermore, the culture cell system expressing
OAT1 was revealed to be useful for the prediction of the nephrotoxicity
of -lactam antibiotics.
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