A BUDESONIDE PRODRUG ACCELERATES TREATMENT OF COLITIS IN RATS

Although oral glucocorticoids are the treatment of choice for moderate to severe ulcerative pancolitis, their systemic side effects and adre nal suppression account for considerable morbidity. An oral glucocorti coid-conjugate (prodrug), budesonide-beta-D-glucuronide, which is not absorbed in the small intestine but is hydrolysed by colonic bacterial and mucosal beta-glucuronidase to release free budesonide into the co lon was synthesised. The objective of this study was to compare treatm ent with budesonide-beta-D-glucuronide with treatment with free budeso nide by examining: (1) the healing of experimental colitis and (2) the extent of adrenal suppression. Pancolitis was induced with 4% acetic acid. Animals were then randomised to receive oral therapy for 72 hour s with (1) budesonide-beta-D-glucuronide, (2) free budesonide, or (3) vehicle. Drug efficacy and colitic healing was determined by measuring gross colonic ulceration, myeloperoxidase activity, and in vivo colon ic fluid absorption. Adrenal suppression was determined by measuring p lasma adrenocorticotrophic hormone and serum corticosterone. Vehicle-t reated colitis animals had gross ulceration, increased myeloperoxidase activity, and net colonic fluid secretion, Treatment with oral budeso nide-beta-D-glucuronide accelerated all measures of colitis healing at a fourfold lower dose than did free budesonide. Furthermore, treatmen t with budesonide-beta-D-glucuronide did not result in adrenal suppres sion whereas free budesonide treatment did. A newly synthesised orally administered glucocorticoid-conjugate accelerates colitis healing wit h limited adrenal suppression. Development of an orally administered c olon-specific steroid delivery system represents a novel approach to i nflammatory bowel disease treatment.