Colonic delivery of dexamethasone from a prodrug accelerates healing of colitis in rats without adrenal suppression.
OBJECTIVE
Dexamethasone-beta-D-glucuronide, a colon-specific prodrug of dexamethasone, may be useful in the treatment of ulcerative colitis and Crohn's colitis. The aim of this study was to evaluate colonic delivery and efficacy of this prodrug in the rat.


METHODS
Distribution of dexamethasone in luminal contents and tissues of the gastrointestinal tract and in plasma was measured after oral administration of dexamethasone-beta-D-glucuronide or free dexamethasone. Efficacy of the prodrug and free drug was tested in an acetic acid-induced rat colitis model. Healing of induced colitis was assessed by measuring net intestinal fluid absorption, colonic surface area of ulceration, histology, and myeloperoxidase activity. Glucocorticosteroid toxicity was evaluated with serum corticosterone and plasma adrenocorticotropic hormone levels.


RESULTS
The drug delivery index (a measure of relative targeting efficiency) was 6.7 and 8.6 in the cecal and colonic mucosa, respectively. The prodrug was significantly more potent than free drug in improving net colonic fluid absorption while significantly reducing surface area of ulceration and histological grade in colitic rats. Treatment with free dexamethasone significantly reduced serum corticosterone levels to subnormal levels, and treatment with the prodrug maintained serum corticosterone and plasma adrenocorticotropic hormone levels near control levels.


CONCLUSIONS
The prodrug dexamethasone-beta-D-glucuronide delivers efficacious amounts of dexamethasone to the large intestine from lower doses than free dexamethasone.
Fedorak
R N
RN
Controlled Release and Biomedical Polymers Department, SRI International, Menlo Park, California, USA.
Haeberlin
B
B
Empey
L R
LR
Cui
N
N
Nolen
H
H
Jewell
L D
LD
Friend
D R
DR
D000302:Adrenal Cortex / Q000187:drug effects*; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D003092:Colitis / Q000188:drug therapy*; D003106:Colon / Q000378:metabolism*; D003345:Corticosterone / Q000097:blood; D003907:Dexamethasone / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005965:Glucuronates / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007408:Intestinal Absorption; D008297:Male; D009195:Peroxidase / Q000378:metabolism; D011355:Prodrugs / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D005965:Glucuronates; D011355:Prodrugs; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D009195:Peroxidase; D003345:Corticosterone