BLOOD-BRAIN BARRIER AND BLOOD-CSF BARRIER

BLOOD-BRAIN BARRIER AND BLOOD-CSF BARRIER Drugs acting in the CNS have to cross the BBB or blood-CSF barrier. These two barriers are formed by brain capillary endothelial cells and epithelial cells of the choroid plexus, respectively. Recent studies have shown that this is not only a static anatomical barrier but also a dynamic one in which efflux transporters play a role (Begley and Brightman, 2003; Sun et al., 2003). P-glycoprotein was identified initially as an efflux transporter, and it extrudes its substrate drugs on the luminal membrane of the brain capillary endothelial cells into the blood. Thus, recognition by P-glycoprotein as a substrate is a major disadvantage for drugs used to treat CNS diseases. In addition to P-glycoprotein, there is accumulating evidence for 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 the blood-CSF barrier and include the members of organic anion transporting polypeptide (OATP1A4 and OATP1A5) and organic anion transporter (OAT3) families (Kikuchi et al., 2004; Mori et al., 2003). They facilitate the uptake process of organic compounds such as b-lactam antibiotics, statins, p-aminohippurate, H2 antagonists, and bile acids on the plasma membrane facing the brain-CSF. The transporters involved in the efflux on the membranes that face the blood still remain to be identified, although several candidate primary active transporters, such as MRP and BCRP, already have been proposed. Members of the organic anion transporting polypeptide family also mediate uptake from the blood on the plasma membrane facing blood. Further clarification of influx and efflux transporters in the barriers will enable delivery of CNS drugs efficiently into the brain while avoiding undesirable CNS side effects and help to define the mechanisms of drug-drug interactions and interindividual differences in the therapeutic CNS effects.