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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Rapid Elimination of Cefaclor from the Cerebrospinal Fluid Is Mediated by a Benzylpenicillin-Sensitive Mechanism Distinct from Organic Anion Transporter 3

Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (M.K., H.K.,Y.S.); and Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Tokyo, Japan (H.E.)

The purpose of this study was to investigate the carrier-mediated elimination of cephalosporins from the cerebrospinal fluid (CSF) via the choroid plexus. Cefaclor and cefalexin are structural analogs with similar lipophilicity, differing by only one functional group (cefaclor, –Cl; cephalexin, –CH₃), and they are substrates of rat peptide transporter PEPT2 with similar transport activities. However, cefaclor was cleared from the CSF more rapidly than cefalexin after intracerebroventricular administration (the elimination rate constants were 0.11 and 0.050 min^-1, respectively). The elimination of cefaclor from the CSF was inhibited by benzylpenicillin, but not by glycylsarcosine (GlySar), whereas GlySar, but not benzylpenicillin, had an inhibitory effect on the elimination of cefalexin from the CSF. The uptake of cefaclor by the freshly isolated rat choroid plexus was saturable, with a K_m value of 250 µM, and the uptake clearance corresponding to saturable components accounts for the major part of the in vivo clearance from the CSF (17 versus 26 µl/min, respectively). The uptake of cefaclor by the choroid plexus was inhibited by benzylpenicillin, but not by GlySar. However, the inhibitory effect of benzylpenicillin was weaker than expected from its own K_m value, and furthermore, organic anion transporter (Oat)3 substrates (cimetidine or p-aminohippurate) had no effect. These results suggest that cefaclor and cefalexin are eliminated from the CSF by different transporters, and rapid elimination of cefaclor from the CSF is accounted for by a benzylpenicillin-sensitive mechanism distinct from Oat3. A slight modification of a single chemical group of cephalosporins can greatly affect the contribution of the transporters involved, and their duration in the CSF.

Address correspondence to: Dr. Yuichi Sugiyama, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan. E-mail: kusuhara{at}mol.f.u-tokyo.ac.jp

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