INVOLVEMENT OF P-GLYCOPROTEIN IN AN IN-VITRO BLOOD-BRAIN-BARRIER MODEL

The P-glycoprotein (P-gp) multidrug transporter is present at the lumi nal face of the brain capillary endothelial cells that contribute to t he blood-brain barrier. To study its role in transendothelial anticanc er drug transport, we made use of a co-culture system formed of bovine brain capillary endothelial cells and astrocytes which allows the in vitro maintenance of specialized properties of the brain endothelial c ells, including expression of P-gp as assessed by Northern and Western blot analyses. Vinblastine, an anticancer drug substrate for P-gp and known not to enter the brain, was found to be poorly transferred acro ss the endothelial cell monolayer. This low vinblastine transport was however strongly increased in the presence of verapamil, a well known P-gp blocker. Moreover, verapamil was shown to increase the accumulati on of the anticancer drug in the brain endothelial cells through inhib ition of drug efflux. These results suggest that P-gp activity evidenc ed in the co-culture model is involved in the low transendothelial tra nsport of vinblastine, thus supporting the conclusion that P-gp expres sed at the blood-brain barrier level may prevent xenobiotics, includin g anticancer drugs, from entering the central nervous system.