Dose-dependent gastrointestinal absorption of 5-fluorouracil in rats in vivo.

Dose-dependent gastrointestinal absorption of 5-fluorouracil (5-FU) was kinetically evaluated in rats in vivo by analyzing gastrointestinal disposition after oral administration, where a linear model assuming first-order gastric emptying followed by first-order intestinal absorption was fitted to remaining fraction versus time profiles for the stomach and small intestine to estimate the rate constants of gastric emptying (kg) and intestinal absorption (Ka). With an increase in dose from 1.5 nmol/rat (low dow) to 15 mumol/rat (high dose), the Ka decreased from 5.95 to 0.55 min-1, suggesting the involvement of carrier-mediated transport. This study is the first to demonstrate the dose-dependent gastrointestinal absorption of 5-FU in vivo, though it has long been suggested in situ and in vitro. Meanwhile, at both the low and high doses, the Kg values, which were unaffected by dose (0.069 and 0.082 min-1, respectively, for the low and high doses), were smaller than the Ka values by an order of magnitude or more and the recovery of 5-FU was negligible, compared with that of inulin (a nonabsorbable marker), in the most distal segment of ileum. These results suggest that, regardless of dose, 5-FU is highly absorbable in a gastric emptying-limited manner. Thus, well-publicized bioavailability problems (low and erratic) of 5-FU may be attributable to extensive and variable first-pass metabolism rather than poor and variable gastrointestinal absorption.