BLOOD-BRAIN-BARRIER FUNCTION OF P-GLYCOPROTEIN

Recent advances in studies on the blood-brain barrier (BBB) transport of xenobiotics, as well as nutrients and neuroactive agents, have led to a change in the classical concept that the BBB is highly impermeabl e for hydrophilic compounds, but permeable for lipophilic ones. The BB B is no longer regarded as a static lipoidal membrane barrier of endot helial cells, but rather is considered to be a dynamic interface that has physiological functions for the specific and selective entry of va rious chemicals into the brain and efflux from the brain, as well as d egradative enzyme activities. This review deals with drug efflux from the brain mediated by P-glycoprotein (P-gp), an ATP-dependent pump whi ch is expressed at the luminal side of normal brain capillary endothel ial cells. Studies using in vitro-cultured brain capillary endothelial cells, in vivo cerebral vascular perfusion, brain microdialysis and m dr1a gene-deficient mice have clarified that active efflux by P-gp res ults in very low effective permeability from the circulating blood to the brain for cyclosporin A, Vinca alkaloids (vincristine and vinblast ine), doxorubicin, rhodamine-123 and digoxin. A detailed understanding of the efflux mechanism would be very helpful for targeting drugs to the brain, or for reduction of BBB penetration of peripherally active drugs in order to minimize side effects in the central nervous system.