Therapeutic switching of sulpiride, an anti-psychotic and prokinetic drug, to an anti-colitic drug using colon-specific drug delivery.

To test whether sulpiride (SP), an anti-psychotic and prokinetic drug, shows beneficial effects on experimental murine colitis, a colon-targeted prodrug of SP, 5-(aminoethanoylsulfamoyl)-N-[(1-ethylpyrrolidin-2-yl)methyl]-2-methoxybenzamide (glycylsulpiride (GSP)), was synthesized and its colonic delivery and therapeutic activity against 2,4-dinitrobenzenesulfonic acid (DNBS)-induced rat colitis were assessed. Synthesis of GSP was verified by infrared and proton nuclear magnetic resonance spectroscopy. GSP was converted to SP when incubated with the cecal contents but not when incubated with the small intestinal contents. The percent conversion was about 50.5% at 6 h and 67.7% at 10 h. Colonic delivery of GSP was examined by comparison with sulfasalazine (SSZ), a colon-specific prodrug of 5-aminosalicylic acid currently used for the treatment of inflammatory bowel disease. The two prodrugs accumulated similar concentrations of the corresponding parent drugs in the cecum at 2, 4, and 6 h after oral gavage. Although oral gavage of GSP released millimolar level of SP in the large intestine, SP was hardly detected in the blood. GSP improved colonic damage score and reduced myeloperoxidase activity up to 80.5% in the inflamed colon in a dose-dependent manner. Moreover, GSP was able to reduce the levels of inflammatory mediators in the inflamed colon. Overall, the anti-colitic effectiveness of GSP and SSZ was similar. In conclusion, colonic delivery of SP ameliorates DNBS-induced colitis in rats with no significant systemic absorption of SP. Thus, colon-targeted SP may be therapeutically switched to an anti-colitic drug.