Synthesis and intestinal metabolism of ursodeoxycholic acid conjugate with an antiinflammatory agent, 5-aminosalicylic acid.
5-Aminosalicylic acid conjugate of ursodeoxycholic acid was synthesized in above 90% yield by adding a basic solution of 5-aminosalicylic acid into the mixed anhydride formed with ursodeoxycholic acid and ethyl chloroformate. The 5-aminosalicylic acid conjugate of ursodeoxycholic acid was poorly secreted into the bile and was deconjugated with cholylglycine hydrolase and Clostridium perfringens, that deconjugate naturally occurring glycine and taurine conjugates of bile acids. However, ursodeoxycholic acid 5-aminosalicylic acid conjugate was not absorbed from the duodenum but was concentrated in the colon where it was partially hydrolyzed by the intestinal bacteria to ursodeoxycholic acid and 5-aminosalicylic acid. We believe that this unique conjugation of ursodeoxycholic acid with 5-aminosalicylic acid may facilitate the transport of both 5-aminosalicylic acid and ursodeoxycholic acid to the colon and may be useful for the treatment of colonic inflammatory bowel diseases, ulcerative colitis and Crohn's disease.
Department of Medicine and Liver Center, University of Medicine and Dentistry-New Jersey Medical School, Newark 07103, USA.
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D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000378:metabolism* / Q000627:therapeutic use; D001693:Biological Transport, Active; D003016:Clostridium perfringens / Q000378:metabolism; D003111:Colonic Polyps / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000378:metabolism; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000382:microbiology; D019804:Mesalamine / Q000138:chemical synthesis* / Q000378:metabolism* / Q000627:therapeutic use; D051381:Rats; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D019804:Mesalamine; D014580:Ursodeoxycholic Acid; D000581:Amidohydrolases; C023154:choloylglycine hydrolase