Distinct carbohydrates influenced the in vitro permeation of the somatostatin analogue octapeptide octreotide through Caco-2 cell monolayers. Apical addition of 20 mM D-glucose or D-xylose resulted in a 2.3- or 3.4-fold increased octreotide permeation, respectively. However, supplementation with 20 mM L-glucose or 20 mM D-fructose showed no permeation enhancement. Basolateral addition of D-glucose or D-xylose had no significant effect on octreotide permeation. Apical medium supplementation with D-glucose or D-xylose increased permeation of the extracellular marker [14C]polyethylene glycol 4000, indicating that both carbohydrates directly affected the paracellular route of octreotide absorption. Presence of 1 mM phlorizin decreased octreotide permeation through monolayers in the presence of glucose on average by 12.8%, suggesting that the Na(+)-dependent glucose cotransporter might be partially involved in the enhancement of the absorption process of octreotide. Octreotide was absorbed from ligated jejunal loops of rat small intestine with an absolute absorption efficiency of about 0.3%. Coadministration of D-glucose of D-xylose resulted in a 2.2- or 1.9-fold increased absorption of octreotide, whereas D-fructose showed no effect. When the peptide was given in the presence of glucose and 1 mM phlorizin, a significant reduction of absorption enhancement could be observed. Phlorizin did not inhibit octreotide absorption, when the peptide was given in the absence of glucose. The data suggest that in vivo the active transepithelial flux of solutes such as glucose contributes to the enhancement of peptide absorption.