PURPOSE: To determine concentration-dependent P-gp-mediated efflux across the luminal membrane of endothelial cells at the blood-brain barrier (BBB) in rats. METHODS: The transport of radiolabeled colchicine and vinblastine across the rat BBB was measured with or without PSC833, a well known P-gp inhibitor, and within a wide range of colchicine and vinblastine concentration by an in situ brain perfusion. Thus, the difference of brain transport achieved with or without PSC833 gives the P-gp-mediated efflux component of the compound transported through the rat BBB. Cerebral vascular volume was determined by coperfusion with labeled sucrose in all experiments. RESULTS: Sucrose perfusion indicated that the vascular space was close to normal in all the studies, indicating that the BBB remained intact. P-gp limited the uptake of both colchicine and vinblastine, but the compounds differ in that vinblastine inhibited its own transport. Vinblastine transport was well fitted by a Hill equation giving IC50 at approximately 71 microM, a Hill coefficient (n) approximately 2, and a maximal efflux velocity Jmax of approximately 9 pmol s(-1) g(-1) of brain. CONCLUSIONS: P-gp at the rat BBB may carry out both capacity-limited and capacity-unlimited transport, depending on the substrate, with pharmacotoxicologic significance for drug brain disposition and risk of drug-drug interactions.
PURPOSE: To determine concentration-dependent P-gp-mediated efflux across the luminal membrane of endothelial cells at the blood-brain barrier (BBB) in rats. METHODS: The transport of radiolabeled colchicine and vinblastine across the rat BBB was measured with or without PSC833, a well known P-gp inhibitor, and within a wide range of colchicine and vinblastine concentration by an in situ brain perfusion. Thus, the difference of brain transport achieved with or without PSC833 gives the P-gp-mediated efflux component of the compound transported through the rat BBB. Cerebral vascular volume was determined by coperfusion with labeled sucrose in all experiments. RESULTS:Sucrose perfusion indicated that the vascular space was close to normal in all the studies, indicating that the BBB remained intact. P-gp limited the uptake of both colchicine and vinblastine, but the compounds differ in that vinblastine inhibited its own transport. Vinblastine transport was well fitted by a Hill equation giving IC50 at approximately 71 microM, a Hill coefficient (n) approximately 2, and a maximal efflux velocity Jmax of approximately 9 pmol s(-1) g(-1) of brain. CONCLUSIONS:P-gp at the rat BBB may carry out both capacity-limited and capacity-unlimited transport, depending on the substrate, with pharmacotoxicologic significance for drug brain disposition and risk of drug-drug interactions.
Authors: C Cordon-Cardo; J P O'Brien; D Casals; L Rittman-Grauer; J L Biedler; M R Melamed; J R Bertino Journal: Proc Natl Acad Sci U S A Date: 1989-01 Impact factor: 11.205
Authors: A M Taylor; J Storm; L Soceneantu; K J Linton; M Gabriel; C Martin; J Woodhouse; E Blott; C F Higgins; R Callaghan Journal: Br J Pharmacol Date: 2001-12 Impact factor: 8.739
Authors: M Zeeshan Qaiser; Diana E M Dolman; David J Begley; N Joan Abbott; Mihaela Cazacu-Davidescu; Delia I Corol; Jonathan P Fry Journal: J Neurochem Date: 2017-08-03 Impact factor: 5.372