Transporter-mediated permeation of drugs across the blood-brain barrier

Drug distribution into the brain is strictly regulated by the presence of t he blood-brain barrier (BBB) that is formed by brain capillary endothelial cells. Since the endothelial cells are connected to each other by tight jun ctions and lack. pores and/or fenestrations, compounds must cross the membr anes of the cells to enter the brain from the bloodstream. Therefore, hydro philic compounds cannot cross the barrier in the absence of specific mechan isms such as membrane transporters or endocytosis. So, for efficient supply of hydrophilic nutrients, the BBB is equipped with membrane transport syst ems and some of those transporter proteins have been shown to accept drug m olecules and transport them into brain. In the present review, we describe mainly the transporters that are involved in drug transfer across the BBB a nd have been molecularly identified. The transport systems described includ e transporters for amino acids, monocarboxylic acids, organic cations, hexo ses, nucleosides, and peptides. Most of these transporters function in the direction of influx from blood to brain; the presence of efflux transporter s from brain to blood has also been demonstrated, including P-glycoprotein, MRPs, and other unknown transporters. These efflux transporters seem to be functional for detoxication and/or prevention of nonessential compounds fr om entering the brain. Various drugs are transported out of the brain via s uch efflux transporters, resulting in the decrease of CNS side effects for drugs that have pharmacological targets in peripheral tissues or in the red uction of efficacy in CNS because of the lower delivery by efflux transport . To identify the transporters functional at the BBB and to examine the pos sible involvement of them in drug transports by molecular and physiological approaches will provide a rational basis for controlling drug distribution to the brain. (C) 2000 Wiley-Liss, Inc.