COLONIC DELIVERY OF PEPTIDE AND PROTEIN DRUGS - CONSIDERATION OF INTRACELLULAR PROTEOLYTIC-ENZYMES

Degradation of insulin and insulin-like growth factor I by rat colon e nterocytes was studied. Immunoprecipitation studies using the monoclon al antibody to insulin-degrading enzyme suggested that insulin degrada tion by colonic mucosal homogenate was mainly due to insulin-degrading enzyme whilst insulin-like growth factor I degradation was nor. Cytos olic proteasome-like activities were involved in insulin-like growth f actor I and insulin degradation, but only to a minor extent. Further, inhibitors of insulin-degrading enzyme greatly inhibited insulin degra dation by colonic mucosal homogenate and significantly improved the tr ansport of insulin monomers across the colon epithelium. It is conclud ed that insulin-degrading enzyme limits insulin absorption in the colo n, and that effective, safe inhibitors of insulin-degrading enzyme or stable, potent insulin analogues are needed in order to achieve useful absorption, and that neither insulin-degrading enzyme nor proteasome contributes, to a substantial extent, to insulin-like growth factor I degradation by colonic enterocytes.