11d • General discussion
Why Peptides Have Low Oral Bioavailability – Skool Summary
The Problem:
Oral peptide bioavailability is typically <1–2%. Your gut is built to destroy them.
The 4 Barriers:
- Stomach Acid (pH 1.5–3.5) – Breaks peptide bonds and unfolds structures.
- Proteolytic Enzymes – Pepsin (stomach), trypsin/chymotrypsin (intestine), and brush border peptidases systematically chop peptides into fragments.
- Epithelial Barrier – Tight junctions block molecules >200 Da. Passive diffusion fails for peptides >500 Da. PepT1 only transports di/tripeptides – useless for larger therapeutics.
- First-Pass Metabolism – Liver extracts 90%+ of what little survives intestinal absorption.
The Exception:
Oral semaglutide achieves ~1% bioavailability using SNAC permeation enhancer – but this is the exception, not the rule.
Bottom Line:
Subcutaneous injection bypasses all barriers. Oral delivery remains a formulation nightmare.
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Why Peptides Have Low Oral Bioavailability – Skool Summary
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