PT - JOURNAL ARTICLE AU - Hong Shen AU - Richard F. Keep AU - Yongjun Hu AU - David E. Smith TI - PEPT2 (<em>Slc15a2</em>)-Mediated Unidirectional Transport of Cefadroxil from Cerebrospinal Fluid into Choroid Plexus AID - 10.1124/jpet.105.090654 DP - 2005 Dec 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 1101--1108 VI - 315 IP - 3 4099 - http://jpet.aspetjournals.org/content/315/3/1101.short 4100 - http://jpet.aspetjournals.org/content/315/3/1101.full SO - J Pharmacol Exp Ther2005 Dec 01; 315 AB - Cefadroxil is a cephalosporin antibiotic used in the treatment of infection. However, cerebrospinal fluid (CSF) concentrations of cefadroxil and other aminocephalosporins are not adequate for the treatment of bacterial meningitis. To evaluate the relevance of PEPT2 in affecting the exposure of aminocephalosporins in brain, we investigated the transport properties of cefadroxil at the blood-CSF interface using primary-cultured epithelial cells and isolated whole tissues of choroid plexus. Our results indicated that cefadroxil was preferentially taken up from the apical as opposed to basal side of the monolayer (5-fold), and its apical uptake was stimulated by an inwardly directed proton gradient. The concentration-dependent apical uptake of cefadroxil was characterized by a high-affinity/low-capacity transport system (Km = 39.0 ± 22.7 μM; Vmax = 22.9 ± 6.6 pmol/mg/min) and a nonsaturable component (Kd = 0.15 ± 0.01 μl/mg/min); in contrast, only a nonsaturable component was found for the basal uptake of cefadroxil (Kd = 0.14 ± 0.01 μl/mg/min). The apical-to-basal transepithelial transport of 2 μM cefadroxil was greater than its basal-to-apical transport, but no differences were observed in directionality when 5 mM concentrations of cefadroxil were studied. Moreover, the cellular efflux of cefadroxil was not saturable in either direction (i.e., to apical or basal side). Finally, no differences were observed in the choroid plexus tissue efflux of 2 μM cefadroxil from wild-type and PEPT2 null mice. These findings demonstrate that PEPT2 has an important role in limiting the exposure of cefadroxil in CSF. Located at the apical membrane of choroid plexus epithelium, PEPT2 acts in a unidirectional (as opposed to bidirectional) manner in transporting cefadroxil from CSF into the cell. The American Society for Pharmacology and Experimental Therapeutics