Role of efflux transport across the blood-brain barrier and blood- cerebrospinal fluid barrier on the disposition of xenobiotics in the central nervous system

The disposition of hydrophilic organic and cations in the central nervous system (CNS) was studied in relation to the transport properties across the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier, using β-lactam antibiotics and cimetidine as model compounds. The concentration profiles for cefodizime in the rat CNS were analyzed using a spatially distributed model. 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 (ECF) and across the ependymal surface into the CSF. In in situ and in vivo experiments, we found that the β-lactam antibiotics are transported across the BBB via a carrier-mediated mechanism. In addition, by analyzing the ligand amount remaining in the brain after microinjection into the cerebral cortex (brain efflux index method), it was clarified that some organic anions are also eliminated from the brain ECF into the blood across the BBB via a specific mechanism. The organic anions are also eliminated from the CSF by the bulk flow and by the active transport system in the choroid plexus which forms the blood-CSF barrier. Comparison of kinetic parameters determined in in vivo and in vitro experiments revealed thai (1) the choroid plexus is the predominant site for the elimination of β-lactam antibiotics from the CSF and (2) 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 β-lactam antibiotics in the choroid plexus. New quinolones (such as fleroxacin) are also transported by the mechanism shared by β-lactam antibiotics. Transport properties of cimetidine, a prototypic organic cation, in the choroid plexus was also characterized in in vivo, in situ and in vitro experiments. Although cimetidine was transported by a specific mechanism, no inhibitory effect of tetraethylammonium, N¹-methylnicotinamide, or choline was observed. In contrast, a mutual inhibition between cimetidine and benzylpenicillin transport was observed. Other examples for such interactions are also summarized, although the molecular mechanism for the transport still remains to be clarified.