TRANSPORT OF CYCLOSPORINE-A ACROSS THE BRAIN CAPILLARY ENDOTHELIAL-CELL MONOLAYER BY P-GLYCOPROTEIN

P-glycoprotein, a multidrug transporter protein, exists in the brain c apillary endothelium. To study the function of P-glycoprotein in brain capillary endothelium as a barrier against cyclosporin A, we examined the interaction of cyclosporin A with P-glycoprotein expressed in cul tured brain capillary endothelial cells (MBEC4). P-glycoprotein of MBE C4 specifically bound [I-125]iodoaryl azidoprazosin, and the binding w as inhibited by cyclosporin A and vincristine. Intracellular accumulat ion of cyclosporin A in MBEC4 was about one-third the amount accumulat ed in mouse aortic endothelial cells (MAEC3), a cell line that did not express P-glycoprotein. The reduced accumulation of cyclosporin A in MBEC4 was increased by verapamil, a competitive inhibitor of transport function of P-glycoprotein. Cyclosporin A was preferentially transpor ted from basal to apical side when the cell monolayer of MBEC4 was for med; however this transendothetial transport was not observed across c ell monolayer of MAEC3. Verapamil inhibited the transendothelial trans port of cyclosporin A across the MBEC4 monolayer. Thus P-glycoprotein in brain capillary endothelium could transport cyclosporin A across th e endothelium from the basal to the apical side. These observations su ggest that P-glycoprotein is involved in the complex function of the b lood-brain barrier as a secretory detoxifying transporter of cyclospor in A.