BUDESONIDE-BETA-D-GLUCURONIDE - A POTENTIAL PRODRUG FOR TREATMENT OF ULCERATIVE-COLITIS

Budesonide-beta-D-glucuronide is a potentially useful orally administe red prodrug for the treatment of colonic inflammatory bowel disease. B udesonide is a topically active glucocorticosteroid that exhibits low oral bioavailability (15%) in humans and laboratory animals. Oral deli very of budesonide to the inflamed tissues of the large intestine as i ts glucuronide prodrug should lead to locally high concentrations of a ctive drug. Following liberation and absorption of the active drug, a large portion should be inactivated due to hepatic metabolism. Budeson ide-beta-D-glucuronide was chemically stable in solutions at pHs of 1. 5, 4.5, 6.5, and 7.4 at 37 degrees C. The enzymatic lability of the pr odrug was assessed in luminal contents and mucosa obtained from conven tional, germ-free, and colitic rats under in vitro conditions. There w as a substantial change in glycosidase activity between the small inte stine (proximal and distal portions) and the cecum in both conventiona l and colitic rat luminal contents. Luminal hydrolytic activity was to w along the entire rat gastrointestinal tract of germ-free rats. Mucos al glycosidase activity was relatively low along the entire gastrointe stinal tract of all three types of rats. The hydrolysis of prodrugs bu desonide-beta-D-glucuronide and dexamethasone-beta-D-glucuronide in hu man fecal samples from patients with ulcerative colitis and normal vol unteers was also measured. There were no statistically significant dif ferences between the normal and colitic fecal samples for hydrolysis o f the either prodrug or between the relative rates of hydrolysis of th e two prodrugs. Hydrolysis rates of the prodrugs were about two orders of magnitude less in human fecal samples compared with those in cecal and colonic contents from the rat.