A NOVEL COLON-SPECIFIC STEROID PRODRUG ENHANCES SODIUM-CHLORIDE ABSORPTION IN RAT COLITIS

A recently synthesized novel colon-specific dexamethasone prodrug, dex amethasone-beta-D-glucuronide, delivers efficacious amounts of dexamet hasone to the colon with limited adrenal suppressive effects. During e xperimentally induced colitis in rats, the dexamethasone prodrug is si gnificantly more potent than free dexamethasone in improving colonic f luid and electrolyte absorptive injury. The present studies examined w hether the improvement in colonic absorption seen with the prodrug occ urred as a consequence of alterations in sodium and chloride epithelia l transport. The efficacy of the dexamethasone prodrug and free dexame thasone were tested in an acetic acid-induced rat model of colitis. He aling of the induced colitis was assessed by measuring net colonic flu id absorption and surface area ulceration. Transmural unidirectional f luxes of Na-22 and Cl-36 across sheets of colonic mucosa were measured in Ussing chambers. Treatment of colitis with the prodrug delivered a sixfold higher concentration of dexamethasone to the colon than did t reatment with the free drug. The prodrug accelerated healing of coliti s by returning in vivo colonic fluid absorption to normal and virtuall y eliminated colonic macroscopic ulceration, whereas the free drug did not. In vitro transmural fluxes demonstrated that, in addition to rep air of mucosal integrity, the prodrug enhanced electroneutral sodium c hloride absorption over and above that seen in control animals or afte r treatment with the free drug. Both the prodrug and the free drug lim ited theophylline-mediated net chloride and sodium secretion, an effec t that would be consistent with the antidiarrheal effect induced by th ese drugs in vivo. The results suggest that treatment of experimentall y induced colitis with the novel colon-specific prodrug, dexamethasone -beta-D-glucuronide, has distinct mucosal healing and antidiarrheal ad vantages over administration of its parent, free dexamethasone. Specif ically, dexamethasone prodrug treatment enhances sodium chloride absor ptive effects and limits adenosine 3',5'-cyclic monophosphate-mediated secretion of colonic epithelia.