Distribution of drugs into the brain is strictly regulated by the presence of the blood-brain barrier that is formed by brain capillary endothelial cells. Since the endothelial cells are connected to each other by tight junctions and lack pores and/or fenestrations, compounds must cross the membranes of the cells to enter the brain from the bloodstream. The blood–brain barrier forms an interface between the circulating blood and the brain and possesses various carrier-mediated transport systems for small molecules to support and protect central nervous system functions. For example, the blood-to-brain influx transport systems supply nutrients, such as glucose and amino acids. Consequently, xenobiotic drugs recognized by influx transporters are expected to have high permeability across the blood brain barrier. On the other hand, efflux transporters, including ATP-binding cassette transporters such as P-glycoprotein located at the luminal membrane of endothelial cells, function as clearance systems for metabolites and neurotoxic compounds produced in the brain. Drugs recognized by these transporters are expected to show low Blood Brain Barrier permeability and low distribution to the brain. Because of the physiological nature of the blood brain barrier, transport of chemical compounds between blood and brain has been widely believed to occur by means of passive diffusion, depending upon the lipophilicity of the compounds. However, discrepancies exist between the lipophilicity and apparent blood brain barrier permeation properties in many cases, such as hydrophilic drugs and these discrepancies can be ascribed to the existence of multiple mechanisms of drug transport through the blood brain barrier. So, for efficient supply of drugs and endogenous substances, the blood brain barrier is equipped with membrane transport systems and some of those transporter proteins have been shown to accept drug molecules and transport them into brain. Molecular identification and functional analysis of influx transport proteins (from blood to brain) and efflux transport proteins (from brain to blood) have progressed rapidly. Therefore, the blood brain barrier is now considered to be a dynamic interface that controls the influx and efflux of a wide variety of substances, including endogenous nutrients and exogenous compounds such as drugs, to maintain a favorable environment for the central nervous system. This review describes mainly the transporters that are involved in drug transfer across the blood brain barrier and have been molecularly identified. The transport systems described include transporters for amino acids, monocarboxylic acids, organic cations, hexoses, nucleosides, and peptides, as well as on strategies to increase drug delivery into the brain by blocking efflux transport protein function, or to reduce central nervous system side effects by modulating blood brain barrier transport processes. This review also will discuss the role of the blood brain barrier in various neuroinflammatory diseases.
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