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This offers several potential benefits: Avoids first-pass metabolism : Unlike swallowed medications that must pass through the liver, sublingual absorption delivers drugs directly to the bloodstream Bypasses stomach acid : GLP-1 peptides are degraded by digestive enzymes, so avoiding the stomach could improve stability Rich vascular network : The area under the tongue has extensive blood vessels that allow rapid absorption However, research on peptide delivery through oral mucosa reveals significant challenges: Peptides like semaglutide and tirzepatide have molecular weights around 4000 Da (compounds above 500 Da generally show poor permeability) Salivary and mucosal proteases degrade peptides before they can cross the epithelial barrier Continuous saliva production dilutes and washes away the medication Studies with insulin showed only 1-2% bioavailability via buccal/sublingual routes without absorption enhancers The key question: Do compounded ODT formulations overcome these barriers

This mechanism may be particularly relevant for patients who had significant insulin resistance before starting GLP-1 therapy