THE INTESTINAL UPTAKE OF ENZYMATICALLY-STABLE PEPTIDE DRUGS IN RATS AS INFLUENCED BY D-GLUCOSE IN-SITU

In previous in situ and in vivo rat perfusion studies, the intestinal absorption of several low molecular weight drugs was increased by the presence of luminal D-glucose. The intent of this study was to determi ne the potential of this fed-state effect to improve the intestinal up take of poorly permeable, small peptide and peptide-like drugs. Jejuna l wall permeabilities (Pw) of di-(D-kyotorphin), tri(cephradine), hex a-(growth hormone releasing peptide, GHRP-6) and octa(octreotide, a so matostatin analogue) peptides and corresponding net water fluxes were determined in rats using an in situ single pass perfusion technique. G lucose was shown to enhance the uptake of the smaller (di- and tri-) p eptides but not the larger peptides despite the fact that glucose elic ited a significant net water absorption with each of the four peptide drugs. It is concluded that glucose enhances jejunal permeabilities of smaller peptides by solvent drag and the enhancement is limited in si tu by peptide molecular size. The studies with nonmetabolizable 3-O-me thylglucose suggest that the augmentation of the proton gradient acros s the transmucosal membrane by glucose contributes to the carrier-medi ated transport observed with the smaller peptides.