Human organic anion transporter hOAT3 is a potent transporter of cephalosporin antibiotics, in comparison with hOAT1

We examined the substrate specificity of human organic anion transporter (hOAT) I and hOAT3 for various cephalosporin antibiotics, cephaloridine, cefdinir, cefotiam, ceftibuten, cefaclor, ceffizoxime, cefoselis and cefazolin by using HEK293 cells stably transfected with hOAT1 or hOAT3 cDNA (HEK-hOAT1, HEK-hOAT3). Additionally, we examined the uptake of various compounds by these transfectants. The mRNA level of hOAT3 in HEK-hOAT3 was about three-fold that of hOAT1 in HEK-hOAT1. Functional expression of hOAT1 and hOAT3 was confirmed by the uptake of p-[C-14]aminohippurate and [H-3]estrone sulfate, respectively. p-[C-14]Aminohippurate, [H-3]estrone sulfate, [C-14]captopril, [H-3]methotrexate, [H-3]ochratoxin A, [H-3]leucovorin and [H-3]cimetidine were shown to be substrates for hOAT1 and hOAT3, and [H-3]dehydroepiandrosterone sulfate was shown to be a substrate for hOAT3. All cephalosporin anitibiotics tested were shown to inhibit the uptake of p-[C-14]aminohippurate and [H-3]estrone sulfate via hOAT1 and hOAT3, respectively, in a dose-dependent manner, and the IC50 values of these antibiotics, except for cefaclor, for the hOAT1-mediated uptake of p[C-14]aminohippurate were within four-fold of those for the hOAT3-mediated uptake of [H-3]estrone sulfate. The uptake of cephaloridine, cefdinir and cefotiam by HEK-hOAT3 was 35-50-fold greater than that by control cells. Moreover, the accumulation of the other cephalolsporin antibiotics was significantly greater in HEK-hOAT3 than in control cells. In contrast, the uptake of these antibiotics by HEK-hOAT1 was within two-fold of that by control cells. In conclusion, hOAT3 plays a more important role than hOAT1 in the renal secretion of cephalosporin antibiotics. (c) 2005 Elsevier Inc. All rights reserved.