Improvement of intestinal absorption of peptides by glycosylation

Abstract

Major obstacles to the oral administration of peptide drugs are their low transmembrane permeability and enzymatic degradation in the gastrointestinal tracts. We glycosylated insulin (INS) to try to solve these problemes. When the derivative, B1-Phe monosubstituted p-(succinylamido)phenyl-α-D-glucopyranoside (SAPG)substituted insulin (SAPG-INS), was administered intraintestinally to rats, it showed a greater hypoglycemic effect than the native bovine insulin. One of the causes of this effect was considered to be the interaction of SAPG-INS with the D-glucose transporter. To investigate more clearly the possibility whether a glycosylated peptide is transported by the Na⁺, D-glucose cotransporter, we synthesized ¹²⁵I-labeled SAPG-Gly-Gly-Tyr-Arg (SAPG-GGYR) and examined its uptake to BBMV by a rapid filtration technique. In the presence of Na⁺-gradient inward to BBMV, the amount of SAPG-GGYR taken up to BBMV was significantly increased in conparison with that in the absence of Nat-gradient. These findings suggested that the glycosylated tetra-peptide is transported by the Na⁺ dependent D-glucose cotransporter. Consequently it is suggested that the glycosylation of peptide drugs increases the resistance to enzymatic degradation and is useful for the improvement of its intestinal absorption.