USE OF URSODEOXYCHOLIC ACID CONJUGATES AS A CARRIER OF 5-AMINOSALICYLIC ACID TO DELIVER TO THE COLONIC REGION: COMPARISON WITH SALAZOSULFAPYRIDINE IN FED RATS

Yorinobu Maeda*, Ryuji Kyan, Akira Shigenaga, Masaya Ohta, Takeshi Goromaru and Teruo Murakami

5-Aminosalicylic acid (5-ASA) is an anti-inflammatory drug widely used to treat ulcerative colitis, an inflammatory bowel disease in the colonic region. The targetability of 5-ASA to the colonic region after oral administration was compared between salazosulfapyridine, a prodrug of 5-ASA azo bonded with sulfapyridine, and 5-ASA combined with ursodeoxycholic acid (UDCA) conjugates in fed rats. The following 5-ASA-UDCA derivatives were synthetized: 5-ASA-UDCA, 5’-ASA-UDCA-3-glucuronide (5-ASA-UDCA-3G), 5’-ASA-UDCA-3-sulfate (5-ASA-UDCA-3S), and 5’-ASA-UDCA-3,7-disulfate (5-ASA-UDCA-DS). These 5-ASA-UDCA and 5-ASA-UDCA conjugates were stable in the biological samples such as plasma, intestinal mucosa, liver, and feces’ homogenates. In contrast, they were split and released 5-ASA by cholylglycine (bile acid) hydrolase, whereas the hydrolysis rates of 5-ASA-UDCA-DS and 5-ASA-UDCA-3S were slow. In rats’ everted gut sac study, 5-ASA-UDCA, but not other 5-ASA-UDCA conjugates, showed site-specific active membrane permeability in the lower ileum. In fed rats, these 5-ASA prodrugs were administered orally and mucosal concentrations of 5-ASA and N-acetyl metabolite (AC-5-ASA) were measured along the gastrointestinal tract 8 h after administration. 5-ASA-UDCA and 5-ASA-UDCA-3G, as well as salazosulfapyridine, showed higher total concentrations of 5-ASA and AC-5-ASA in the colonic-region membranes. The colonic distribution of 5-ASA from 5-ASA-UDCA-DS and 5-ASA-UDCA-3S was low. Taken together, 5-ASA-UDCA-3G, being not absorbed actively in the ileum in rats, was thought to be a feasible prodrug in the targeted delivery of 5-ASA to the colonic region, although further study is necessary.