A novel colon-specific steroid prodrug enhances sodium chloride
absorption in rat colitis.
Fedorak, Richard N, Ningren Cui, David R Friend, Karen L Madsen,
Lonnie R Empey.
Division of Gastroenterology, Department of Medicine, University of
Alberta, Edmonton, Alberta, Canada and Stanford Research Institute,
Menlo Park, California
APStracts 2:0042G, 1995.
A recently synthesized novel colon-specific dexamethasone prodrug,
dexamethasone-[beta]-D-glucuronide, delivers efficacious amounts of
dexamethasone to the colon with limited adrenal suppressive effects.
During experimentally-induced colitis in rats the dexamethasone
prodrug is significantly more potent than free dexamethasone in
improving colonic fluid and electrolyte absorptive injury. The
present studies examined whether the improvement in colonic
absorption seen with the prodrug occurred as a consequence of
alterations in sodium and chloride epithelial transport. The efficacy
of the dexamethasone prodrug and free dexamethasone were tested in an
acetic acid-induced rat model of colitis. Healing of the induced
colitis was assessed by measuring net colonic fluid absorption and
surface area ulceration. Transmural unidirectional fluxes of 22Na and
36Cl across sheets of colonic mucosa were measured in Ussing
Chambers. Treatment of colitis with the prodrug delivered 6-fold
higher concentration of dexamethasone to the colon than did treatment
with the free drug. The prodrug accelerated healing of colitis by
returning in vivo colonic fluid absorption to normal and virtually
eliminated colonic macroscopic ulceration, whereas, the free drug did
not. In vitro transmural fluxes demonstrated that in addition to
repair of mucosal integrity the prodrug enhanced electroneutral
sodium chloride absorption over and above that seen in control
animals or following treatment with the free drug. Both the prodrug
and the free drug limited theophylline-mediated net chloride and
sodium secretion, an effect that would be consistent with the
antidiarrheal effect induced by these drugs in vivo. The results
suggest that treatment of experimentally-induced colitis with the
novel colon-specific prodrug, dexamethasone-[beta]-D-glucuronide, has
distinct mucosal healing and antidiarrheal advantages over
administration of its parent, free dexamethasone. Specifically,
dexamethasone prodrug treatment enhances sodium chloride absorptive
effects and limits cAMP-mediated secretion of colonic epithelia.
Received 18 August 1994; accepted in final form 21 February 1995.
APS Manuscript Number G306-4.
Article publication pending Am. J. Physiol. (Gastrointest. Liver
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 21 March 1995.