Brain uptake and anticancer activities of vincristine and vinblastine are restricted by their low cerebrovascular permeability and binding to plasma constituents in rat

Abstract

Unidirectional blood-brain barrier transfer of the lipophilic anticancer agents vincristine and vinblastine was studied in anesthetized rats, using an isolated, in situ brain perfusion technique. Drug binding to plasma constituents was also measured. Despite the high lipophilicity of these agents (the log octanol/physiological saline partition coefficient equalled 2.14 and 1.68, respectively), the cerebrovascular permeability-surface area product, PA, of vincristine in plasma was only 0.49 x 10(-4) ml s-1 g-1 for parietal cerebral cortex, whereas that of vinblastine was too low for determination. These values are similar to those of water-soluble, poorly diffusible nonelectrolytes. The PAs were significantly higher in the absence of plasma protein, being 1.24 x 10(-4) and 5.36 x 10(-4) ml s-1 g-1, respectively. Even these values, determined by brain perfusion of protein-free buffer, were lower than would be expected from the lipophilicity of the agents. The results suggest that additional factors, such as steric hindrance and molecular charge distribution, related to the chemical and geometric structure and the large size of vincristine and vinblastine (molecular weight, 825 and 814 daltons, respectively) restrict their passage across the blood-brain barrier. As a consequence of their paradoxically low permeability at the blood-brain barrier and restrictive binding to plasma and blood constituents, doses of both agents that cause significant inhibition of extracerebral Walker 256 carcinosarcoma tumor implants in rat have no effect on tumor located in the brain.

The Design, Synthesis, and Biological Evaluation of New Paclitaxel Analogs With the Ability to Evade Efflux by P-Glycoprotein

“…The in situ rat brain perfusion data correlated well with our in vitro permeability data, showing that Tx-67 permeation across the BBB was in fact substantially greater than the permeation of Taxol into rat brains. Our Taxol data were comparable to perfusion data for other anticancer drugs such as vincristine and vinblastine (Greig et al, 1990).…”

Brain drug delivery and blood–Brain barrier transport

“…Levin has estimated the threshold of lipid-mediated transport through the BBB as being between 400 and 657 Da (43). This threshold was corroborated by Grieg and coworkers (44), who showed that vincristine or vinblastine have BBB permeability coefficients that are much reduced compared to what would be expected based on the lipid solubility of these compounds, which have a molecular weight of 814-825 Da. Another example is cyclosporin which has a molecular weight of 1200 ( Fig.…”

Development of lipophilic anticancer agents for the treatment of brain tumors by the esterification of water-soluble chlorambucil

“…tered systemically [13,25,26]. A major determinant for a water-soluble agent is its cerebrovascular permeability, in the absence of a facilitated transport mechanism [27].…”