A glucocorticoid prodrug facilitates normal mucosal function in rat colitis without adrenal suppression.
OBJECTIVE
Glucocorticoids remain the foundation of therapy for acute ulcerative colitis despite systemic side effects that limit their use. Prodrugs that selectively deliver glucocorticoids to the colon may lower the required dose and side effects. The aim of this study was to assess the efficacy of a newly synthesized glucocorticoid-dextran prodrug.


METHODS
Novel glucocorticoid-dextran prodrug conjugates in which dexamethasone and methylprednisolone were attached to dextran were synthesized using the dicarboxylic acid linkers, succinate and glutarate. The efficacy of the dextran prodrug conjugates and their free glucocorticoids was tested in an acetic acid-induced model of colitis. Repair of the colitis and mucosal function was assessed by measuring net intestinal fluid absorption, macroscopic ulceration, and myeloperoxidase activity. Glucocorticoid toxicity was evaluated by measuring plasma adrenocorticotropic hormone and serum corticosterone levels.


RESULTS
The prodrug dexamethasone-succinate-dextran was nine times more potent and dexamethasone-glutarate-dextran three times more potent than free dexamethasone in accelerating mucosal repair. Similarly, methylprednisolone-succinate-dextran was four times more potent than free methylprednisolone. The dextran prodrug conjugates affected adrenocorticotropic hormone and corticosterone levels only at the highest doses in contrast to free dexamethasone and methylprednisolone, which caused marked adrenal suppression at all doses.


CONCLUSIONS
The results show that recently synthesized glucocorticoid-dextran prodrug conjugates can be administered orally to facilitate mucosal repair in rat colitis without adrenosuppression.
McLeod
A D
AD
Department of Pharmacy, School of Pharmacy, University of California, San Francisco.
Fedorak
R N
RN
Friend
D R
DR
Tozer
T N
TN
Cui
N
N
D000311:Adrenal Glands / Q000187:drug effects*; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D003092:Colitis / Q000188:drug therapy* / Q000378:metabolism; D003106:Colon / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D003911:Dextrans / Q000494:pharmacology / Q000627:therapeutic use; D005938:Glucocorticoids / Q000494:pharmacology* / Q000627:therapeutic use; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009195:Peroxidase / Q000378:metabolism; D011355:Prodrugs / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley
D003911:Dextrans; D005938:Glucocorticoids; D011355:Prodrugs; D000324:Adrenocorticotropic Hormone; D009195:Peroxidase; D003345:Corticosterone