First-Pass Metabolism
The phenomenon where a drug administered orally is partially metabolised in the gut wall and liver before reaching the systemic circulation, reducing its bioavailability. Peptides are extensively degraded during first-pass metabolism by gastrointestinal proteases and hepatic enzymes, which is why most require injection.
Technical Context
When an oral drug is absorbed from the GI tract, it enters the portal venous system and passes through the liver before reaching systemic circulation. The liver's metabolic enzymes (CYP450 family for small molecules, proteases for peptides) and the gut wall's enzymes can extensively degrade the drug during this first pass. For oral peptides, first-pass destruction is compounded by pre-absorptive degradation in the GI lumen (by pepsin, trypsin, chymotrypsin) and poor epithelial permeability. The combined effect yields oral bioavailability typically <1% for peptides. Oral semaglutide's SNAC formulation partially addresses GI degradation but not hepatic first-pass, which is why the oral dose (14mg) is much higher than the SC dose (1mg for equivalent glycaemic effect).