CONTROL OF INTESTINAL ABSORPTION OF BIOLOGICALLY ACTIVE PEPTIDES BY VARIOUS PROTEASE INHIBITORS

Abstract

The effects of protease inhibitors on the intestinal absorption of insulin and human calcitonin were investigated in situ in closed small and large intestinal loops in rats. The intestinal absorption of insulin and human calcitonin was evaluated by its hypoglycemic and hypocalcemic effects, respectively. When insulin alone was administered into small or large intestinal loops, no marked hypoglycemic response was observed in either region. However, a significant hypoglycemic effect was obtained following large intestinal administration of insulin with various protease inhibitors, whereas we found little hypoglycemic effect following small intestinal co-administration of insulin with these protease inhibitors. In addition, when the luminal surface was washed with saline solution, we did not observe the regional difference in promoting insulin absorption by these inhibitors. Similar results were also noted in the effects of these inhibitors on the intestinal absorption of human calcitonin. In the stability experiments, insulin and human calcitonin were rapidly degraded in the small intestinal fluid and homogenates of the small or large intestinal mucosae. Further, these protease inhibitors were effective for improving the stability of these peptides in the intestinal homogenates. In conclusion, these findings indicate that the protease inhibitors increase the intestinal stability of these peptides, thereby improving their absorption from the gut. These results would give us basic information for developing the oral dosage form of peptide drugs.