TAXOL TRANSPORT BY HUMAN INTESTINAL EPITHELIAL CACO-2 CELLS

Taxol (paclitaxel) belongs to a new class of antimicrotubule anticance r drugs with clinical activity against common solid tumors and acute l eukemias, Preclinical studies have suggested that taxol is not absorbe d after oral doses, However, whether the observed low oral bioavailabi lity is the result of poor absorption or extensive presystemic hepatic metabolism is not clear, For this reason, we studied the transepithel ial flux of taxol, using the human colonic cell line Caco-2 as a model , The cells were grown to confluency on permeable polycarbonate membra ne inserts, to permit flux experiments after loading of [H]taxol on ei ther 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 b asolateral to the apical side was 4-10 times greater than that from th e apical to the basolateral side, Whereas the absorptive transport app eared linearly related to the taxol concentration (0.5-20 mu M), the e fflux was saturable, The apparent K-M of the active efflux component w as 16.5 mu M. Verapamil (50 mu M) significantly decreased the active t ransport component, These data support the conclusion that rapid passi ve diffusion of taxol through the intestinal epithelium is partially c ounteracted by the action of an outwardly directed efflux pump, presum ably P-glycoprotein. However, the relatively high apparent permeabilit y coefficient for the apical to basolateral taxol transport (4.4 +/- 0 .4 x 10(-6) cm/s; N = 17) suggests that the drug may still be effectiv ely absorbed in the intestinal tract.