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Pharm Res. 2003 Oct;20(10):1607-11.

In vivo saturation of the transport of vinblastine and colchicine by P-glycoprotein at the rat blood-brain barrier.

Author information

1
INSERM U26, Hôpital Fernand Widal, 200 Rue du Faubourg Saint-Denis, 75475 Paris Cedex 10, France. Salvatore.Cisternino@fwidal.inserm.fr

Abstract

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.

PMID:
14620515
[Indexed for MEDLINE]

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