| Abstract
| - The purpose of this work was to introduce a chemical modification into the paclitaxel (Taxol)structure to reduce interactions with the product of the multidrug resistant type 1 (MDR1)gene, P-glycoprotein (Pgp), resulting in improved blood−brain barrier (BBB) permeability.Specifically, a taxane analogue, Tx-67, with a succinate group added at the C10 position ofTaxol, was synthesized and identified as such a candidate. In comparison studies, Tx-67 hadno apparent interactions with Pgp, as demonstrated by the lack of enhanced uptake ofrhodamine 123 by brain microvessel endothelial cells (BMECs) in the presence of the agent.By contrast, Taxol exposure substantially enhanced rhodamine 123 uptake by BMECs throughinhibition of Pgp. The transport across BMEC monolayers was polarized for both Tx-67 andTaxol with permeation in the apical to basolateral direction greater for Tx-67 and substantiallyreduced for Taxol relative to basolateral to apical permeation. Taxol and cyclosporin Atreatments also did not enhance Tx-67 permeation across BMEC monolayers. In an in situ ratbrain perfusion study, Tx-67 was demonstrated to permeate across the BBB at a greater ratethan Taxol. These results demonstrate that the Taxol analogue Tx-67 had a reduced interactionwith Pgp and, as a consequence, enhanced permeation across the blood−brain barrier in vitroand in situ.
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