Abstract
Taxol (paclitaxel) belongs to a new class of antimicrotubule anticancer drugs with clinical activity against common solid tumors and acute leukemias. Preclinical studies have suggested that taxol is not absorbed after oral doses. However, whether the observed low oral bioavailability is the result of poor absorption or extensive presystemic hepatic metabolism is not clear. For this reason, we studied the transepithelial flux of taxol, using the human colonic cell line Caco-2 as a model. The cells were grown to confluency on permeable polycarbonate membrane inserts, to permit flux experiments after loading of [3H]taxol on either the apical or basolateral side. The flux of taxol across the Caco-2 cell layer was linear with time for up to 3 hr. The flux from the basolateral to the apical side was 4–10 times greater than that from the apical to the basolateral side. Whereas the absorptive transport appeared linearly related to the taxol concentration (0.5–20 μM), the efflux was saturable. The apparent KM of the active efflux component was 16.5 μM. Verapamil (50 μM) significantly decreased the active transport component. These data support the conclusion that rapid passive diffusion of taxol through the intestinal epithelium is partially counteracted by the action of an outwardly directed efflux pump, presumably P-glycoprotein. However, the relatively high apparent permeability coefficient for the apical to basolateral taxol transport (4.4 ± 0.4 × 10−6 cm/s; N = 17) suggests that the drug may still be effectively absorbed in the intestinal tract.
Footnotes
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Send reprint requests to: Dr. Thomas Walle, Department of Pharmacology, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425.
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This study was supported in part by National Institutes of Health grant CA63386 and by the Hollings Cancer Center, and these results were presented at the 6th European Meeting of the International Society for the Study of Xenobiotics in Gothenburg, Sweden (June 30 to July 3, 1997).
- Abbreviations used are::
- HBSS
- Hanks’ balanced salt solution
- Papp
- apparent permeability coefficient
- HEPES
- N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid)
- CYP or P450
- cytochrome P450
- Received August 27, 1997.
- Accepted December 11, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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