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 determine the potential of this fed-state effect to improve the intestinal uptake of poorly permeable, small peptide and peptide-like drugs. Jejunal wall permeabilities (Pw*) of di-(D-kyotorphin), tri-(cephradine), hexa-(growth hormone releasing peptide, GHRP-6) and octa-(octreotide, a somatostatin analogue) peptides and corresponding net water fluxes were determined in rats using an in situ single-pass perfusion technique. Glucose was shown to enhance the uptake of the smaller (di- and tri-) peptides but not the larger peptides despite the fact that glucose elicited 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 situ by peptide molecular size. The studies with nonmetabolizable 3-O-methylglucose suggest that the augmentation of the proton gradient across the transmucosal membrane by glucose contributes to the carrier-mediated transport observed with the smaller peptides.
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Department of Pharmaceutics, College of Pharmacy, University of Michigan, Ann Arbor 48109-1065.
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Monkhouse
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Fleisher
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D019325:3-O-Methylglucose; D000818:Animals; D002515:Cephradine / Q000493:pharmacokinetics; D004723:Endorphins / Q000493:pharmacokinetics; D005947:Glucose / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000187:drug effects*; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism*; D008757:Methylglucosides / Q000494:pharmacology; D015282:Octreotide / Q000493:pharmacokinetics; D009842:Oligopeptides / Q000493:pharmacokinetics*; D010539:Permeability; D051381:Rats
D004723:Endorphins; D008757:Methylglucosides; D009842:Oligopeptides; C019448:kyotorphin; D019325:3-O-Methylglucose; C041048:growth hormone releasing hexapeptide; D002515:Cephradine; D005947:Glucose; D015282:Octreotide