Transport of a Hydrophilic Paclitaxel Derivative, 7-Xylosyl-10-Deacetylpaclitaxel, by Human Intestinal Epithelial Caco-2 Cells

Abstract

7-Xylosyl-10-deacetylpaclitaxel is an active compound used in traditional Chinese medicine to treat cancer. However, pharmacokinetic studies yielded low plasma concentrations of 7-xylosyl-10-deacetylpaclitaxel after its oral administration in preclinical trials. Therefore, we investigated whether the observed low oral bioavailability of this compound is due to poor absorption. We studied the transepithelial flux of 7-xylosyl-10-deacetylpaclitaxel using the human colonic cell line Caco-2 as a model and found out that its flux (at a concentration range of 0.5–20 µM) across the Caco-2 cell layer was linear with time for up to 3 hr. The apparent maximal concentration (K_M) of the active efflux component was 93.4 µM. Verapamil (50 µM) and tetrandrine (25 µM) significantly decreased the active transport component. These data support the conclusion that rapid passive diffusion of 7-xylosyl-10-deacetylpaclitaxel through the intestinal epithelium is partially counteracted by the action of an outwardly directed efflux pump, presumably P-glycoprotein. The relatively high apparent permeability coefficient (P _app) for the apical to basolateral 7-xylosyl-10-deacetylpaclitaxel transport (16.3 ± 6.3 × 10⁻⁶ cm/s; n = 3) suggests that the drug may still be effectively absorbed in the intestinal tract.

Key words

7‐xylosyl‐10‐deacetylpaclitaxel - Caco‐2 - absorption ‐P‐glycoprotein - Taxus cuspidate - Taxaceae

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