Dose-Dependent Gastrointestinal Absorption of 5-Fluorouracil in Rats in Vivo

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Dose-dependent gastrointestinal absorption of 5-fluorouracil (5-FU) was kinetically evaluated in rats in vivo by analyzing gastointestinal 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 (k_g) and intestinal absorption (k_a). With an increase in dose from 1.5 nmol/rat (low dose) to 15 μmol/rat (high dose), the k_a 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 vivtro. Meanwhile, at both the low and high doses, the k_g values, which were unaffected by dose (0.069 and 0.082 min^<-1>, respectively, for the low and high doses), were smaller that the k_a 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 problem (low and erratic) of 5-FU may be attributable to extensive and variable first-pass metabolism rather than poor and variable gastrointestinal absorption.
社団法人日本薬学会の論文
1996-11-15

Dose-Dependent Gastrointestinal Absorption of 5-Fluorouracil in Rats in Vivo

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