In vivo saturation of the transport of vinblastine and colchicine by P-glycoprotein at the rat blood-brain barrier.
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.[1]References
- In vivo saturation of the transport of vinblastine and colchicine by P-glycoprotein at the rat blood-brain barrier. Cisternino, S., Rousselle, C., Debray, M., Scherrmann, J.M. Pharm. Res. (2003) [Pubmed]
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