COLONIC DELIVERY OF DEXAMETHASONE FROM A PRODRUG ACCELERATES HEALING OF COLITIS IN RATS WITHOUT ADRENAL SUPPRESSION

Background/Aims: Dexamethasone-beta-D-glucuronide, a colon-specific pr odrug of dexamethasone, may be useful in the treatment of ulcerative c olitis and Crohn's colitis. The aim of this study was to evaluate colo nic delivery and efficacy of this prodrug in the rat. Methods: Distrib ution of dexamethasone in luminal contents and tissues of the gastroin testinal tract and in plasma was measured after oral administration of dexamethasone-beta-D-glucuronide or free dexamethasone. Efficacy of t he prodrug and free drug was tested in an acetic acid-induced rat coli tis model. Healing of induced colitis was assessed by measuring net in testinal fluid absorption, colonic surface area of ulceration, histolo gy, and myeloperoxidase activity. Glucocorticosteroid toxicity was eva luated with serum corticosterone and plasma adrenocorticotropic hormon e levels. Results: The drug delivery index (a measure of relative targ eting efficiency) was 6.7 and 8.6 in the cecal and colonic mucosa, res pectively. The prodrug was significantly more potent than free drug in improving net colonic fluid absorption while significantly reducing s urface area of ulceration and histological grade in colitic rats. Trea tment with free dexamethasone significantly reduced serum corticostero ne levels to subnormal levels, and treatment with the prodrug maintain ed serum corticosterone and plasma adrenocorticotropic hormone levels near control levels. Conclusions: The prodrug dexamethasone-beta-D-glu curonide delivers efficacious amounts of dexamethasone to the large in testine from lower doses than free dexamethasone.