Efflux transport systems at the blood-brain barrier and blood CSF barrier

Drugs acting in the central nervous system (CNS) have to cross the blood-brain barrier (BBB) and/or blood-cerebrospinal fluid barrier (BCSFB). These two barriers are formed by brain capillary endothelial cells and choroid plexus epithelial cells. P-glycoprotein (P-gp) was initially identified as an efflux transporter at the BBB. It extrudes its substrate drugs into the blood, and acts as one of barrier functions against invasion of xenobiotics into the central nervous system. Thus, recognition by P-gp as a substrate is a major disadvantage for drugs used to treat CNS disease. In addition to P-gp, accumulating evidence has revealed the presence of efflux transport systems for anionic drugs. The transporters involved in the efflux transport of organic anions from the CNS are being identified in the BBB and BCSFB, and include the members of organic anion transporting polypeptides (Oatp1a4 and Oatp1a5) and organic anion transporter (Oat3) which are involved in the efflux of amphipathic and hydrophilic organic anions, respectively. The transporters located on the membranes facing the blood still remain to be identified although several candidate primary active transporters, such as MRP and BCRP, have already been proposed. Further clarification of influx and efflux transporters in the barriers will enable us to deliver drugs efficiently into the brain and to understand the mechanisms of drug-drug interactions and interindividual differences in the therapeutic CNS effects and/or adverse effects caused by drugs. The present manuscript summarizes the recent advance in the characterization of efflux transport systems at the BBB and BCSFB from our laboratory and others.