EVALUATION OF THE ROLE OF P-GLYCOPROTEIN IN IVERMECTIN UPTAKE BY PRIMARY CULTURES OF BOVINE BRAIN MICROVESSEL ENDOTHELIAL-CELLS

The P-glycoprotein efflux system located on the apical membrane of bra in capillary endothelial cells functions as part of the blood-brain ba rrier. In this study, primary cultures of bovine brain microvessel end othelial cells (BMECs) were investigated for the presence of a P-glyco protein system and its contribution in regulating ivermectin distribut ion across the blood-brain barrier. Results of rhodamine 123 uptake st udies with cyclosporin A and verapamil as substrates indicated that a functional efflux system was present on BMECs. Immunoblot analysis wit h the C219 monoclonal antibody to the product of the multidrug resista nt member 1(MDR1) gene also confirmed the expression of MDR1 in the BM ECs. Unbound ivermectin was shown to significantly increase the uptake of rhodamine 123 in BMECs, however, the drug only modestly enhanced t he transcellular passage of rhodamine. The results of these studies af firmed that unbound ivermectin is an inhibitor of the MDR1 efflux syst em in BMECs.