Drug transfer across the blood-brain barrier and improvement of brain delivery

The blood-brain barrier is formed by the endothelial cells of the brain cap illaries. Its primary characteristic is the impermeability of the capillary wall due to the presence of complex tight junctions and a low endocytic ac tivity. Essential nutrients are delivered to the brain by selective transpo rt mechanisms, such as the glucose transporter and a variety of amino acid transporters. Although most drugs enter the brain by passive diffusion thro ugh the endothelial cells depending on their lipophilicity, degree of ioniz ation, molecular weight, relative brain tissue and plasma bindings, some ot hers can use specific endogenous transporters. In such cases, binding compe tition on the transporter with endogenous products or nutrients can occur a nd limits drug transfer. The blood-brain barrier can be a major impediment for the treatment of diseases of the central nervous system, since many dru gs are unable to reach this organ at therapeutic concentrations. Various at tempts have been made to overcome the limiting access of drugs to the brain , e.g. chemical modification, development of more hydrophobic analogs or li nking an active compound to a specific carrier. Transient opening of the bl ood-brain barrier in humans has been achieved by intracarotid infusion of h ypertonic mannitol solutions or of bradykinin analogs. Another way to incre ase or decrease brain delivery of drugs is to modulate the P-glycoprotein ( P-gp) whose substrates are actively pumped out the cell into the capillary lumen. Many P-gp inhibitors or inducers are available to enhance the therap eutic effects of centrally acting drugs or to decrease central adverse effe cts of peripherally active drugs. (C) Elsevier, Paris.