Why are peptides injected instead of taken orally?

The gastrointestinal tract is not friendly to peptides. Stomach acid at pH 1.5–3.5 hydrolyses peptide bonds, cleaving the peptide into smaller fragments. If the peptide survives the stomach, it meets pancreatic and brush-border peptidases in the small intestine — trypsin, chymotrypsin, carboxypeptidases, aminopeptidases — which are evolved specifically to cleave peptides into individual amino acids for absorption. Whatever peptide fraction survives absorption then passes through the portal vein directly to the liver, where first-pass metabolism reduces it further before it reaches systemic circulation.

The cumulative effect is that oral bioavailability for most peptides is below 1%. For most therapeutic peptides, that fraction is not enough to produce clinical effect at any reasonable oral dose. The pragmatic solution is to bypass the gastrointestinal tract entirely by injecting the peptide subcutaneously or intramuscularly, giving 60–90% bioavailability.

A small number of peptides have been engineered to survive the oral route. Oral semaglutide (Rybelsus) uses enteric coating plus a permeation enhancer (SNAC) that transiently increases gastric epithelial permeability, achieving about 1% oral bioavailability. Combined with a much larger daily dose than the injectable version requires, that fraction produces clinical effect. Cyclosporine is another example of an orally-administered peptide with engineered formulation. But these are exceptions; the pharmacological default remains injection.