COLONIC MUCOSA-SPECIFIC PRO-ANTEDRUGS FOR ORAL TREATMENT OF ULCERATIVE-COLITIS - DESIGN, SYNTHESIS AND FATE OF METHYL 20-GLUCOPYRANOSYLOXYPREDNISOLONATES

Hydrophilic steroid derivatives, methyl 20-beta-glucopyranosyloxypredn isolonates (15 and 16), were synthesized from prednisolone via methyl 20 (R/S)-dihydroprednisolonates (2 and 1) based on a novel colonic muc osa-specific drug delivery system. Optimal conditions for the synthese s of each isomer 1 and 2 were found by the extensive studies on the re action rates from prednisolone under various concentrations of cupric acetate in dry methanol. Their configurations at C-20 in compounds 1 a nd 2 were determined by their formation mechanism. The fate of compoun ds 15 and 16 after the oral administration was examined in rats and gu inea-pigs. The glycosides were stable in the small-intestinal contents , but the glycoside bonds were cleaved by the action of bacteria in th e large-intestinal contents to release compounds 1 and 2, respectively , which were rapidly hydrolysed to the inactive carboxylates in the pl asma. The high recovery of the glycosides and the aglycons in the larg e-intestinal contents after intrajejunal administration of compounds 1 5 and 16 in guinea-pigs proved the glycosides to be poorly absorbed fr om the small intestine. These results suggest that the glycosides 15 a nd 16 may be orally effective 'pro-antedrugs', which specifically expr ess the anti-inflammatory activity in the colonic mucosa with no syste mic effect.