QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.105.090654v1 315/3/1101    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shen, H. Articles by Smith, D. E. Search for Related Content PubMed PubMed Citation Articles by Shen, H. Articles by Smith, D. E.

ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

PEPT2 (Slc15a2)-Mediated Unidirectional Transport of Cefadroxil from Cerebrospinal Fluid into Choroid Plexus

Departments of Pharmaceutical Sciences (H.S., Y.H., D.E.S.) and Neurosurgery and Physiology (R.F.K.), University of Michigan, Ann Arbor, Michigan

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 (K_m = 39.0 ± 22.7 µM; V_max = 22.9 ± 6.6 pmol/mg/min) and a nonsaturable component (K_d = 0.15 ± 0.01 µl/mg/min); in contrast, only a nonsaturable component was found for the basal uptake of cefadroxil (K_d = 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.

Address correspondence to: Dr. David E. Smith, 4302A Upjohn Center, 1310 E. Catherine St., University of Michigan, Ann Arbor, MI 48109-0504. E-mail: smithb{at}umich.edu

This article has been cited by other articles:

				H. Shen, S. M. Ocheltree, Y. Hu, R. F. Keep, and D. E. Smith Impact of Genetic Knockout of PEPT2 on Cefadroxil Pharmacokinetics, Renal Tubular Reabsorption, and Brain Penetration in Mice Drug Metab. Dispos., July 1, 2007; 35(7): 1209 - 1216. [Abstract] [Full Text] [PDF]

				H. Daniel, B. Spanier, G. Kottra, and D. Weitz From Bacteria to Man: Archaic Proton-Dependent Peptide Transporters at Work Physiology, April 1, 2006; 21(2): 93 - 102. [Abstract] [Full Text] [PDF]