Intestinal brush border transport mechanism of 5-fluorouracil in rats.
The intestinal transport mechanism of 5-fluorouracil (5-FU) was investigated in the intestinal everted sacs and brush border membrane vesicles (BBMVs) of rats. In the everted sacs, the initial uptake of 5-FU was apparently Na(+)-dependent, in terms of the inhibition of the uptake by replacing the Na+ in the medium with K+, and also concentration-dependent in the presence of Na+, with a maximum transport rate of 0.74 +/- 0.24 nmol/min/cm and a Michaelis constant of 0.025 +/- 0.018 mM. Passive transport was also significant, with a membrane permeability clearance of 5.9 +/- 0.6 microliters/min/cm. The uptake of 5-FU was inhibited by pyrimidines (uracil and thymine) and 2, 4-dinitrophenol (DNP), a metabolic inhibitor, but not by purines (adenine and guanine), pyrimidine nucleosides (thymidine and uridine), L-alanine or D-glucose. These results suggest the involvement of carrier-mediated transport specific to pyrimidines in intestinal 5-FU transport, and this appeared to satisfy the criteria of Na(+)-dependent secondary active transport. However, in BBMVs, 5-FU uptake was independent of Na+, minimally dependent on concentration and not inhibited by thymine, though slightly inhibited by uracil. 5-FU uptake was also independent of pH, outward HCO3- gradient and valinomycin-induced K+ diffusion potential. Thus, the carrier-mediated transport of 5-FU, or presumably pyrimidines, may require some other factors, which are yet to be identified, in addition to Na+. Alternatively, Na+ may not be prerequisite, and something else may be required in the absence of K+, as suggested from an additional result in everted sacs that the replacement of NaCl in the medium with mannitol failed to inhibit 5-FU uptake.
Yuasa
H
H
Faculty of Pharmaceutical Sciences, Nagoya City University, Japan.
Matsuhisa
E
E
Watanabe
J
J
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics*; D001693:Biological Transport, Active / Q000187:drug effects; D003470:Culture Media; D005472:Fluorouracil / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D008871:Microvilli / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000502:physiology
D000964:Antimetabolites, Antineoplastic; D003470:Culture Media; D012964:Sodium; D005472:Fluorouracil