Colonic mucosa-specific "pro-antedrugs" for oral treatment of ulcerative colitis: design, synthesis and fate of methyl 20-glucopyranosyloxyprednisolonates

Hydrophilic steriod derivatives, methyl 20-β-glucopyranosyloxyprednisolonates (15 and 16), were synthesizd from prenisolone via methyl 20(R/S)-dihydroprednisolonates (2 and 1) based on a novel colonic mucosa-specific drug delivery system. Optimal conditions for the syntheses of each isomer 1 and 2 were found by the extensive studies on the reaction rates from prednisolone under various concentrations of cupric acetate in dry methanol. Their configurations at C-20 in compounds 1 and 2 were determined by their formation mechanism. The fate of compounds 15 and 16 after the oral administration was examined in rats ang guinea-pigs. The glycosides were stable in the small-intestinal contents, but the glycoside bonds were cleaved by the action of bacteria in the large-intestinal contents to release compounds 1 and 2, respectively, which were rapidly hydrolysed to the inactive carboxylates in the plasma. The high recovery of the glycosides and the aglycons in the large-intestinal contents after intrajejunal administration of compounds 15 and 16 may be orally effective 'pro-antedrugs', which specifically express the anti-inflammatory acitivity in the glycosides 15 and 16 may be orally effective 'pro-antedrugs', which specifically express the anti-inflammatory activity in the colonic mucosa with no systemic effect.