Permeability of 5-fluorouracil and prodrugs in Caco-2 cell monolayers.

The toxicity and permeability of 5-fluorouracil (5FU) and 13 5FU prodrugs was investigated in Caco-2 monolayers grown on permeable supports. Only one of the prodrugs (VII) was toxic to the cell monolayers at 1 x 10(-4) M, as assessed by an increased permeability of the cell monolayers to the hydrophilic probe C-14-mannitol. The monolayer integrity was restored after a 4-fold reduction in the concentration of this prodrug. The permeabilities of 5FU and prodrugs increased roughly with the apparent partition coefficients (P-octanol-buffer) (r = 0.74). Attempts to correlate the permeabilities with other single physicochemical parameters such as hydrogen-bonding capacity and solubility resulted in poorer correlations. A slightly better relationship was obtained when the permeability was correlated with the two physicochemical parameters (P-octanol-buffer) and aqueous solubility by multiple linear regression analysis (r = 0.81). The ranking of the permeabilities of four of the compounds previously studied in rabbit colon and rectum was comparable in the cell monolayers and in the intestinal segments. These results indicate that Caco-2 monolayers can be used to predict drug absorption, not only of conventional drugs but also of small prodrugs such as those used here.