P-glycoprotein-mediated transport of morphine in brain capillary endothelial cells

Cell accumulation, transendothelial permeability, and efflux studies were c onducted in bovine brain capillary endothelial cells (BBCECs) to assess the role of P-glycoprotein (P-gp) in the blood-brain barrier (BBB) transport o f morphine in the presence and absence of P-gp inhibitors. Cellular accumul ation of morphine and rhodamine 123 was enhanced by the addition of the P-g p inhibitors N-{4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl) -et hyl]-phenyl}-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918) , verapamil, and cyclosporin A. Positive (rhodamine 123) and negative (sucr ose and propranolol) controls for P-gp transport also were assessed. Morphi ne glucuronidation was not detected, and no alterations in the accumulation of propranolol or sucrose were observed. Transendothelial permeability stu dies of morphine and rhodamine 123 demonstrated vectorial transport. The ba solateral to apical (B:A) fluxes of morphine (50 mu M) and rhodamine (1 mu M) were approximately 50 and 100% higher than the fluxes from the apical to the basolateral direction (A:B), respectively. Decreasing the extracellula r concentration of morphine to 0.1 mu M resulted in a 120% difference betwe en the B:A and A:B permeabilities. The addition of GF120918 abolished any s ignificant directionality in transport rates across the endothelial cells. Efflux studies showed that the loss of morphine from BBCECs was temperature - and energy-dependent and was reduced in the presence of P-gp inhibitors. These observations indicate that morphine is transported by P-gp out of the brain capillary endothelium and that the BBB permeability of morphine may be altered in the presence of P-gp inhibitors. BIOCHEM PHARMACOL 58;6:951-9 57, 1999. (C) 1994 Elsevier Science Inc.