First-Pass Metabolism of 5-Fluorouracil in the Perfused Rat Small Intestine

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The first-pass intestinal metabolism of 5-fluorouracil (5-FU) was investigated by single-pass perfusion of the rat small intestine. At the low concentration of 0.06 mg/ml, the fraction of 5-FU absorbed into (i.e., appeared in) the meenteric venous blood (F_<a, b> was about 50% smaller than the fraction absorbed (disappeared) from the intestinal lumen (F_a), indicating the first-pass extraction of 5-FU in the intestinal mucosa. By addition of uracil (6 mg/ml), the F_a of 5-FU was reduced presumably by competition for the pyrimidine carrier at the process of intestinal uptake (entry into the mucosa). The F_<a, b> was also reduced, but to a lesser extent, resulting in insignificant first-pass extraction. These results suggest that the extraction of 5-FU in the absence of uracil is caused by metabolism and that uracil is a competitor for this pathway. When 5-FU concentration was reiased from 0.06 to 0.6 mg/ml in the absenec of uracil, the F_a was reduced by about 50%, consistent with the suggestion of the involvement of saturable uptake by the pyrimidine carrier, and thereafter remained unchanged at 6 mg/ml. Howeve, since F_<a, b> was also reduced by a similar extent, the intenstinal availability (F_1=F_<a, b>/F_a) was unchanged at about 0.5,indicating that the intestinal first-pass extraction of 5-FU is independent of concentration with the extraction ratio (difference between unity and F_1) of about 0.5 over the wide range of concentration from 0.06 to 6 mg/ml. Thus, the present study demonstrates that the significant first-pass metabolic extraction of 5-FU occurs in the mucosa of the small intestine, supporting our previous suggestion that 5-FU undergoes first-pass metabolism not only in the liver but also in the small intestine after oral administration. Considering that the oral bioavailability of 5-Fu in the human (28%) is reportedly comparable with that in the rat (28%), it is likely that intestinal first-pass metabolism may be significant also in the human. Intestinal first-pass metabolism should be taken into account to explore more efficient and controlled oral 5-FU therapy.
社団法人日本薬学会の論文
1998-08-15

First-Pass Metabolism of 5-Fluorouracil in the Perfused Rat Small Intestine

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