Intestinal 5-fluorouracil absorption: use of Ussing chambers to assess transport and metabolism.
We have employed an in vitro system to study transport and metabolism of organic molecules by gastrointestinal tissues. Such a system would aid in the evaluation of the potential for oral delivery of organic molecules. Transport and metabolism of 5-fluorouracil (5-FU) were studied using rabbit intestinal preparations. Unidirectional fluxes and metabolism were measured in vitro in Ussing chambers under short-circuit conditions. Results from these studies reveal that in ileum, proximal, and distal colon, steady-state fluxes of 5-FU (10 microM added to both bathing solutions) are established after 30 min and remain constant for at least 110 min. Transport of 5-FU under "sink" conditions with 10 microM 5-FU present in the mucosal or serosal bathing solution alone demonstrated similar rates of transport as under "nonsink" conditions. The concentration dependence of 5-FU fluxes indicates that the mucosal (m)-to-serosal (s) flux is composed of both a saturable and a linear component over the range of 1-100 microM in the ileum, whereas the s-to-m flux in the ileum and both fluxes in the colon are linear functions of concentration. Over the concentration range employed and the time course of these studies, 5-FU had no effect on the electrical properties of the ileum or colon. In the ileum, the m-to-s but not the s-to-m flux of 5-FU was reduced by (1) serosal ouabain (0.1 mM); (2) reduction of the bathing solution Na concentration; and (3) addition of uracil, thymine, thymidine, uridine, 2-deoxyuridine, or uridine-5'-monophosphate.(ABSTRACT TRUNCATED AT 250 WORDS)
Smith
P
P
Department of Drug Delivery, Smith Kline and French Research Laboratories, Philadelphia, Pennsylvania 19406-0939.
Mirabelli
C
C
Fondacaro
J
J
Ryan
F
F
Dent
J
J
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003106:Colon / Q000378:metabolism; D005472:Fluorouracil / Q000378:metabolism / Q000493:pharmacokinetics*; D007082:Ileum / Q000378:metabolism; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D011817:Rabbits; D012964:Sodium / Q000378:metabolism
D012964:Sodium; D005472:Fluorouracil