title: P-glycoprotein-mediated transport of morphine in brain capillary endothelial cells.
abstract: Cell accumulation, transendothelial permeability, and efflux studies were conducted in bovine brain capillary endothelial cells (BBCECs) to assess the role of P-glycoprotein (P-gp) in the blood-brain barrier (BBB) transport of morphine in the presence and absence of P-gp inhibitors. Cellular accumulation of morphine and rhodamine 123 was enhanced by the addition of the P-gp inhibitors N-{4-[2-(1,2,3,4-tetrahydro-6,7dimethoxy-2-isoquinolinyl)-ethyl]-phenyl}-9,10-dihydro-5-methoxy-9- carboxamide (GF120918), verapamil, and cyclosporin A. Positive (rhodamine 123) and negative (sucrose and propranolol) controls for P-gp transport also were assessed. Morphine glucuronidation was not detected, and no alterations in the accumulation of propranolol or sucrose were observed. Transendothelial permeability studies of morphine and rhodamine 123 demonstrated vectorial transport. The basolateral to apical (B:A) fluxes of morphine (50 microM) and rhodamine (1 microM) were approximately 50 and 100% higher than the fluxes from the apical to the basolateral direction (A:B), respectively. Decreasing the extracellular concentration of morphine to 0.1 microM resulted in a 120% difference between the B:A and A:B permeabilities. The addition of GF120918 abolished any significant 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.
authors.affiliation: School of Pharmacy, Division of Drug Delivery and Disposition, University of North Carolina at Chapel Hill, 27599-7360, USA.
authors.forename: S P
authors.initials: SP
authors.lastname: Letrent
authors.forename: J W
authors.initials: JW
authors.lastname: Polli
authors.forename: J E
authors.initials: JE
authors.lastname: Humphreys
authors.forename: G M
authors.initials: GM
authors.lastname: Pollack
authors.forename: K R
authors.initials: KR
authors.lastname: Brouwer
authors.forename: K L
authors.initials: KL
authors.lastname: Brouwer
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000701:Analgesics, Opioid / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism; D002196:Capillaries / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D004058:Diffusion; D004730:Endothelium, Vascular / Q000378:metabolism*; D009020:Morphine / Q000378:metabolism / Q000493:pharmacokinetics*; D009022:Morphine Derivatives / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000701:Analgesics, Opioid; D009022:Morphine Derivatives; C035349:morphine-6-glucuronide; D009020:Morphine; C018108:morphine-3-glucuronide