Salcaprozate sodium (SNAC) is the first oral absorption enhancer incorporated into an FDA-approved peptide therapeutic (Rybelsus, oral semaglutide), representing a paradigm shift in oral peptide delivery that overcomes the gastrointestinal barriers historically limiting peptide bioavailability to below 1%.

To examine the mechanism of action, pharmacokinetic profile, and clinical validation of SNAC as a gastric permeation enhancer, synthesizing evidence from preclinical studies through the PIONEER phase 3 program.

Literature review of mechanistic studies including solid-state NMR spectroscopy, molecular dynamics simulations, Caco-2 permeability assays, in vivo pharmacoscintigraphy, and the 10-trial PIONEER clinical program enrolling 9,543 patients with type 2 diabetes.

SNAC achieves gastric transcellular permeation enhancement through a four-step mechanism: localized pH buffering to approximately pH 5, promotion of semaglutide monomerization, concentration-dependent membrane fluidization (43% increase in hydrophobic core fluidity), and fully reversible non-covalent dissociation post-absorption. Oral bioavailability reaches 0.4-1%, sufficient for therapeutic efficacy due to semaglutide's picomolar receptor affinity and week-long half-life.

SNAC represents a technological inflection point for oral peptide delivery, with implications extending beyond GLP-1 agonists to insulin, calcitonin, PTH, and octreotide. Its transcellular mechanism preserves epithelial barrier integrity, distinguishing it from paracellular enhancers.

Provides fundamental understanding of the oral GLP-1 absorption mechanism critical for clinicians counseling patients on Rybelsus dosing requirements and for researchers developing next-generation oral biologics.