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The disposition of hydrophilic drugs in the central nervous system (CNS) was studied in relation to the transport properties across the brain capillaries which form the blood-brain barrier (BBB), and the choroidal epithelial cells which form the blood-cerebrospinal fluid (CSF) barrier, using beta-lactam antibiotics as model compounds. The concentration profiles for cefodizime in the rat CNS were analyzed based on a pharmacokinetic model in which the physiological and anatomical aspects of the CNS were considered. The model analysis revealed that the drug penetration into the CSF after i.v. administration can be accounted for by permeation across the BBB and diffusion through the brain extracellular fluid and across the ependymal surface into the CSF. The drug molecules are eliminated from the CSF by the bulk flow and by the active transport system in the choroid plexus. In in situ and in vivo experiments, we found that the beta-lactam antibiotics are transported across the BBB via a carrier-mediated mechanism. Comparison of kinetic parameters determined in vivo and in vitro experiments revealed (1) that the choroid plexus is the predominant site for the elimination of beta-lactam antibiotics from the CSF and (2) that the isolated choroid plexus can be a useful tool to predict the in vivo elimination clearance. We also found that an anionic exchanger, at least in part, plays a role in the uphill transport of beta-lactam antibiotics in the choroid plexus. Furthermore, the substrate specificity for the anion transporter was examined in the isolated choroid plexus. New quinolones (such as fleroxacin) are also transported by the mechanism shared by beta-lactam antibiotics. Dideoxyinosine, a nucleoside derivative, can be a substrate for the transporter, whereas azidothymidine is recognized, but not transported by the transport system. Transport properties of cimetidine, a prototypic organic cation, in the choroid plexus was also characterized in vivo, in situ and in vitro experiments. An interaction was observed in the transport of cimetidine and that of organic anions. Molecular mechanisms for the CNS transport still remain to be clarified.

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Kinetic Analysis of the Disposition of Hydrophilic Drugs in the Central Nervous System (CNS) : Prediction of the CNS Disposition from the Transport Properties in the Blood-Brain and Blood-Cerebrospinal Fluid Barriers