Research ArticleDRUG MECHANISM

Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist

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Science Translational Medicine  14 Nov 2018:
Vol. 10, Issue 467, eaar7047
DOI: 10.1126/scitranslmed.aar7047

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Assisting absorption

Glucagon-like peptide-1 receptor agonists can help treat type 2 diabetes but must be administered by injection. Toward developing an effective oral therapy, Buckley et al. tested whether coformulating an oral GLP-1 analog, semaglutide, with SNAC, a small fatty acid derivative, improved drug absorption. Unlike most drugs, the coformulation was absorbed in the stomach rather than in the intestine. In animal studies and human trials, SNAC buffered the local pH of the stomach to protect against enzymatic degradation and facilitate transepithelial absorption via the transcellular route. These results suggest that the transient absorption enhancement offered by SNAC coformulation may help develop effective oral peptide–based therapies.

Abstract

Oral administration of therapeutic peptides is hindered by poor absorption across the gastrointestinal barrier and extensive degradation by proteolytic enzymes. Here, we investigated the absorption of orally delivered semaglutide, a glucagon-like peptide-1 analog, coformulated with the absorption enhancer sodium N-[8-(2-hydroxybenzoyl) aminocaprylate] (SNAC) in a tablet. In contrast to intestinal absorption usually seen with small molecules, clinical and preclinical dog studies revealed that absorption of semaglutide takes place in the stomach, is confined to an area in close proximity to the tablet surface, and requires coformulation with SNAC. SNAC protects against enzymatic degradation via local buffering actions and only transiently enhances absorption. The mechanism of absorption is shown to be compound specific, transcellular, and without any evidence of effect on tight junctions. These data have implications for understanding how highly efficacious and specific therapeutic peptides could be transformed from injectable to tablet-based oral therapies.

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