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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Mechanisms of Cefadroxil Uptake in the Choroid Plexus: Studies in Wild-Type and PEPT2 Knockout Mice

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

The choroid plexus uptake of [³H]cefadroxil was studied in peptide transporter 2 (PEPT2) wild-type and null mice as a function of temperature, transport inhibitors, pH, and saturability. At normal pH (7.4) and temperature (37°C), the uptake of 1 µM cefadroxil was reduced by 83% in PEPT2^–/– mice as compared with PEPT2^+/+ mice (p < 0.001). A further reduction was achieved in null animals by reducing the temperature to 4°C, or by adding saturating concentrations of unlabeled cefadroxil or p-aminohippurate (p < 0.05). Glycylsarcosine coadministration could inhibit the uptake of cefadroxil in PEPT2^+/+ mice (p < 0.01) but not PEPT2^–/– mice. Although a proton-stimulated uptake of cefadroxil was demonstrated in PEPT2^+/+ mice (pH 6.5 versus pH 7.4; p < 0.01), no pH dependence was observed in PEPT2^–/– mice. Kinetic parameters for cefadroxil (without p-aminohippurate) in wild-type mice were: V_max = 5.4 pmol/mg/min, K_m = 34 µM, and K_d = 0.0069 µl/mg/min; in the presence of p-aminohippurate, the parameters were: V_max = 4.1 pmol/mg/min, K_m = 27 µM, and K_d = 0.0064 µl/mg/min. In null animals, the kinetic parameters of cefadroxil (without p-aminohippurate) were: V_max = 2.7 pmol/mg/min, K_m = 110 µM, and K_d = 0.0084 µl/mg/min; in the presence of p-aminohippurate, only a K_d = 0.010 µl/mg/min was observed. Based on kinetic and inhibitor analyses, it was determined that (under linear conditions), 80 to 85% of cefadroxil's uptake in choroid plexus is mediated by PEPT2, 10 to 15% by organic anion transporter(s), and 5% by nonspecific mechanisms. These findings demonstrate that PEPT2 is the primary transporter responsible for cefadroxil uptake in the choroid plexus. Moreover, the data suggest a role for PEPT2 in the clearance of peptidomimetics from cerebrospinal fluid.

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

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