A new amino acid derivative of ursodeoxycholate, (N-L-Glutamyl)-UDCA (UDCA-Glu), to selectively release UDCA in the colon.

ABSTRACT

BACKGROUND: Ursodeoxycholic acid (UDCA) is chemoprotective in animal models of colon cancer but results from clinical trials have been less impressive probably because UDCA is rapidly absorbed in the small intestine and little reaches the colon. UDCA-glutamate (Glu), a novel bile acid, was synthesized with the objective of utilizing peptide bond cleavage by brush border enzymes to enhance delivery of UDCA to the colon. MATERIALS AND METHODS: Qualitative and quantitative intestinal intraluminal and fecal bile acid composition measured by mass spectrometry was determined in Fisher rats after intragastric administration of UDCA, or UDCA-Glu for 5 days. The effect of UDCA and UDCA-Glu on bile flow was studied after bile duct canulation. RESULTS: In the small intestine, UDCA was found in higher amounts when UDCA was administered compared with UDCA-Glu (1.50 + or - 0.32 vs. 0.75 + or - 0.12 mg). By contrast, UDCA-Glu administration resulted in a greater delivery of UDCA to the colon. The fecal bile acid composition resembled that of the intraluminal colonic composition and a higher mass of UDCA (unconjugated 3.39 + or - 0.30 mg; conjugated 6.40 + or - 1.03 mg) was found in rats treated with UDCA-Glu compared to those treated with UDCA (2.27 + or - 0.11 and. 0.04 + or - 0.01 mg, respectively), establishing increased delivery of UDCA to the colon. Both bile acids similarly increased bile flow but the initial effect of UDCA was greater than that of UDCA-Glu. CONCLUSION: Conjugation of UDCA to glutamic acid reduces its intestinal absorption and biotransformation resulting in increased colonic delivery of UDCA. UDCA-Glu may have potential application as a pro-drug for enhancing the action of UDCA in the treatment of colonic diseases.