ABSTRACT
The blood-brain barrier (BBB) represents an insurmountable obstacle for most drugs including many essential drugs such as antineoplastic agents, antibiotics, and central nervous system active drugs (1,2). This barrier is formed by the endothelial cells surrounding the brain capillaries, which are linked by tight continuous circumferential junctions that abolish any aqueous paracellular pathways between these cells and greatly restrict the movement of polar solutes across the cerebral endothelium. A barrier function also occurs at the arachnoid membrane and in the ependymal cells surrounding the circumventricular organs of the brain (3-5). Lipophilic drugs may passively diffuse across the brain endothelial cells. However, this mechanism is restricted by molecular weight and especially by extremely effective efflux pumps that include P-glycoprotein (Pgp), sometimes referred to as multidrug resistance protein (MDR), and multiple organic anion transporter (MOAT) (5). Consequently, the BBB essentially comprises the major interface between the blood and the brain and plays a major role in the regulation of the constancy of the internal environment of the brain. However, since the brain is dependent on the blood for the delivery of substrates as well as for the removal of metabolic waste, and owing to the fact that water-soluble components and especially larger molecular weight components including larger lipophilic molecules and particles, cannot enter the brain, special receptors and transporters, as for instance the insulin, transferrin, and low-density lipoprotein (LDL) receptor, exist for the transport of essential substances across the BBB (6). Glucose and amino acids can also access the brain by similar mechanisms (5).
