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 microM; Vmax = 22.9 +/- 6.6 pmol/mg/min) and a nonsaturable component (Kd = 0.15 +/- 0.01 microl/mg/min); in contrast, only a nonsaturable component was found for the basal uptake of
cefadroxil (Kd = 0.14 +/- 0.01 microl/mg/min). The apical-to-basal transepithelial transport of 2 microM
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 microM
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.