title: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Clinica di Gastroenterologia ed Epatologia dell'Università degli Studi di Perugia, Ospedale S.Maria della Misericordia, S.Andrea delle Fratte, 06156 Perugia, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Asciutti
authors.forename: Danilo
authors.initials: D
authors.lastname: Castellani
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Nardi
authors.forename: Olivia
authors.initials: O
authors.lastname: Morelli
authors.forename: Mattia
authors.initials: M
authors.lastname: Clementi
authors.forename: Fabio
authors.initials: F
authors.lastname: Chistolini
authors.forename: Giorgio
authors.initials: G
authors.lastname: Gentili
authors.forename: Kenneth D R
authors.initials: KD
authors.lastname: Setchell
authors.forename: Nancy
authors.initials: N
authors.lastname: O'Connell
authors.forename: Roberto
authors.initials: R
authors.lastname: Pellicciari
authors.forename: Carlo
authors.initials: C
authors.lastname: Clerici
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology*; D002853:Chromatography, Liquid; D003106:Colon / Q000378:metabolism*; D005243:Feces / Q000737:chemistry*; D008401:Gas Chromatography-Mass Spectrometry; D018698:Glutamic Acid / Q000378:metabolism*; D007408:Intestinal Absorption; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives* / Q000378:metabolism*
chemical_list: D001647:Bile Acids and Salts; D018698:Glutamic Acid; D014580:Ursodeoxycholic Acid