PENETRATION OF 5-FLUOROURACIL AND PRODRUGS ACROSS THE INTESTINE OF THE ALBINO RABBIT - EVIDENCE FOR SHIFT IN ABSORPTION SITE FROM THE UPPER TO THE LOWER REGION OF THE GASTROINTESTINAL-TRACT BY PRODRUGS

The penetration of 5-fluorouracil (5-FU) and five of its prodrugs across the duodenum, jejunum, ileum, colon and rectum of the albino rabbit was studied using the modified Ussing chamber. The prodrugs were the 1-ethoxycarbonyl, 1-isopropyloxycarbonyl, 1-butyloxycarbonyl, 1-cyclohexyloxycarbonyl and 1-butyryloxymethyl derivatives of 5-FU. Appearance of 5-FU and its prodrugs on the serosal side was monitored by reversed phase HPLC. 5-FU penetrated the jejunum most readily, followed by the duodenum, ileum, rectum and colon in that order. This rank order of penetration was essentially reversed by all five prodrugs. In particular, all five prodrugs reduced the penetration of 5-FU across duodenal, jejunal and ileal segments by a factor of 3-100, while enhancing its penetration across colonic and rectal segments by a factor of 5-12. The net result was a shift in the principal absorption site of 5-FU from the upper to the lower region of gastrointestinal tract. The prodrugs were as effective as the penetration enhancers sodium glycocholate and EDTA in enhancing the rectal penetration of 5-FU, but perhaps without the liability of local irritation and toxicity associated with most penetration enhancers. The reduction in 5-FU transport across the small intestinal segments by prodrugs may be due to a shift in the pathway of drug penetration from para- to trans-cellular rather than to reduced affinity of the prodrugs for the 5-FU carrier. This possibility remains to be investigated. © 1990.