Bioavailability

Bioavailability (F) is the fraction of an administered dose of a drug that reaches systemic circulation in its active, unchanged form. An intravenous drug has 100% bioavailability by definition — it goes directly into the bloodstream. Every other route is measured against that benchmark.

Why it matters for peptides

Most peptides have extremely poor oral bioavailability — typically less than 1-2%. Three barriers are responsible:

1. Enzymatic degradation. The gastrointestinal tract is designed to break down proteins and peptides. Pepsin in the stomach, trypsin and chymotrypsin in the small intestine, and brush-border peptidases all cleave peptide bonds. A peptide taken orally is treated as food.
2. Poor membrane permeability. Peptides are typically hydrophilic, charged at physiological pH, and too large to passively diffuse across the lipid bilayer of intestinal epithelial cells. The paracellular route (between cells) is restricted by tight junctions.
3. First-pass metabolism. Even if a peptide survives the gut and crosses the intestinal wall, it passes through the liver before reaching systemic circulation. Hepatic enzymes further degrade most peptide structures.

This is why the vast majority of therapeutic peptides are administered by injection — subcutaneous, intramuscular, or intravenous — bypassing all three barriers.

Routes and their bioavailability

| Route | Typical Peptide Bioavailability | Example |

|-------|-------------------------------|---------|

| Intravenous | 100% (by definition) | — |

| Subcutaneous | 60-90% | Semaglutide (Wegovy), insulin |

| Intramuscular | 70-95% | Some vaccine adjuvant peptides |

| Intranasal | 10-30% | Semax, Selank, desmopressin |

| Oral | <1-2% (usually) | Most unmodified peptides |

| Topical | Variable, local only | GHK-Cu, Argireline |

Subcutaneous injection is the dominant route for therapeutic peptides because it combines high bioavailability with patient-friendly self-administration (small needles, no clinic visit required).

The oral semaglutide breakthrough

Oral semaglutide (Rybelsus) is a notable exception to the oral-bioavailability problem. It uses SNAC (sodium N-[8-(2-hydroxybenzoyl)amino] caprylate), an absorption enhancer that:

• Creates a locally alkaline microenvironment in the stomach, protecting semaglutide from pepsin
• Promotes transcellular absorption across gastric epithelium
• Must be taken fasting with minimal water for reliable absorption

Even with SNAC, oral semaglutide's bioavailability is approximately 0.4-1% — vastly lower than injected semaglutide. The dose compensates: oral semaglutide is dosed at 7-14 mg versus 0.5-2.4 mg for the injectable. The clinical efficacy is slightly lower than injectable, but the convenience advantage drives adoption.

Implications for peptide research

Understanding bioavailability clarifies several practical points:

• Oral peptide supplements (collagen peptides, BPC-157 capsules) face the same degradation barriers. Collagen peptides are partially hydrolyzed and may provide amino acid building blocks, but they don't act as intact signaling peptides in the way injectable peptides do.
• Nasal peptides (Semax, Selank) achieve meaningful CNS delivery because the nasal mucosa provides relatively direct access to the brain, but systemic bioavailability remains modest.
• Topical peptides in skincare are designed for local effect — they don't need systemic bioavailability, only penetration to the dermis.

The bioavailability constraint is the fundamental reason the peptide therapeutic landscape is dominated by injectables, and why oral formulations remain the exception rather than the rule.