Bioavailability explained

The fraction that makes it through

Bioavailability (F) is the fraction of an administered dose that reaches systemic circulation in unchanged form. An intravenous dose is by definition 100% bioavailable — it is delivered directly into circulation. A subcutaneous or intramuscular dose has bioavailability typically in the 60–90% range for peptides that are stable in interstitial fluid. An oral dose has to survive stomach acid, pancreatic enzymes, brush-border peptidases, first-pass hepatic metabolism, and intestinal wall transport — and for most peptides the bioavailability after oral administration is below 1%. This overwhelming barrier is the reason essentially every peptide in this catalog is injected rather than swallowed. The exceptions are informative and worth understanding.

The stomach acid barrier

Stomach pH is approximately 1.5–3.5 during active digestion. That pH is corrosive to most peptides through acid-catalysed hydrolysis of peptide bonds — the same chemistry described in the peptide stability guide, but at the extreme end of the pH scale. A peptide that enters the stomach can lose substantial fractions of its intact structure during the 1–4 hours it spends there before passing into the small intestine. Enteric coating (a pH-resistant polymer coating that protects the peptide until it reaches the more neutral small intestine) is one strategy for surviving this step. Oral semaglutide (Rybelsus) uses this approach combined with a permeation enhancer (SNAC — sodium N-[8-(2-hydroxybenzoyl)amino]caprylate) that transiently increases gastric epithelial permeability, achieving about 1% oral bioavailability. That's low, but it's high enough — combined with a large dose — to produce clinical effect.

The peptidase gauntlet

The small intestine and pancreatic secretions contain a rich set of peptidases that cleave peptides into individual amino acids for absorption — trypsin, chymotrypsin, carboxypeptidases, aminopeptidases, and dipeptidases. That is a feature: dietary protein has to be digested into amino acids to be absorbed. It is also the reason therapeutic peptides survive poorly in the gastrointestinal tract. Peptides delivered orally without protection are cleaved into their constituent amino acids like any other protein source, and while those amino acids may nourish the body, the biological activity of the intact peptide is lost. Even peptides that survive stomach acid meet the peptidase gauntlet immediately afterwards. Strategies for surviving this step include peptide backbone modifications that resist cleavage (D-amino acids, N-methylation, unnatural amino acids) and delivery formulations that shield the peptide during transit.

First-pass metabolism

Even a peptide that survives stomach acid and intestinal peptidases faces one more barrier: absorption into the portal venous system delivers it directly to the liver, where a substantial fraction can be metabolised before reaching systemic circulation. This is the 'first-pass effect'. For small-molecule oral drugs, first-pass hepatic metabolism is a well-characterised design consideration — many oral drug candidates fail because their first-pass metabolism is too extensive. For peptides, hepatic uptake and metabolism can also reduce the fraction reaching systemic circulation, though the specifics depend on the peptide. The combination of stomach acid, intestinal peptidases, and first-pass metabolism is why oral bioavailability for most peptides is essentially zero, and why the injectable route dominates the peptide-therapy space.

The alternative routes

Between fully injectable and fully oral, several alternative routes have been developed for specific peptides where the injection format is not ideal. Intranasal delivery bypasses the gastrointestinal tract entirely and can deliver small peptides through the nasal mucosa or (for very small compounds) directly to the brain via the olfactory pathway. Selank, semax and (in earlier development) intranasal PT-141 all use this route. Intranasal bioavailability is typically higher than oral (5–20% for peptides) but lower than injection. Buccal (cheek pouch) and sublingual routes offer similar advantages for a narrower set of peptides. Transdermal delivery for peptides remains largely investigational — peptides are too large and hydrophilic to cross intact skin readily, though microneedle patches are being developed for some applications. The rectal and vaginal mucosae can be used for specific compounds. For most peptides in this catalog, subcutaneous injection remains the pragmatic delivery route.

References

• Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide· Lau J, Bloch P, Schäffer L, et al. · 2015

Links open external, peer-reviewed sources. Healthy Mango does not host trial data.