Research Peptide Bioavailability

Can Peptides Be Administered Orally?

No, most peptide therapies can't be taken orally. Peptides are an important part of food, so the stomach and intestines have enzymes that break them down so they can be absorbed and used by the body as nutrients. Therefore, most peptide-based medications do not survive the passage through the gastrointestinal tract.

Do Oral Peptides Work?

Oral peptides generally don’t work well because they get degraded by the harsh conditions in the stomach and the proteases in GI tract that degrade peptides before they can be absorbed.

Why Can’t You Take Oral Peptides?

You can’t take oral peptides because they don’t survive the stomach's acidic conditions and the GI tract's proteolytic enzymes. Oral peptides get broken down and degraded before they can be absorbed, which dramatically limits their bioavailability.

Peptide Background

Peptides are a class of therapeutic agents with versatile biological functions that frequently require parenteral administration, a delivery route that bypasses the gastrointestinal (GI) system. The most common parenteral method is injection, but alternative routes include nasal inhalation, topical application, suppositories, and ophthalmic drops.

However, oral administration remains the most convenient for patients due to its simplicity and non-invasive nature. Unfortunately, many peptides cannot be taken orally, largely due to challenges with bioavailability, the proportion of the compound that reaches its intended site of action.

This discussion explores the barriers to oral peptide bioavailability and highlights the distinctions between peptides that are orally bioavailable and those requiring parenteral delivery.

Bioavailability in Peptides

Bioavailability quantitatively measures the extent to which a compound reaches its target destination in the body, regardless of the administration route. For peptides, oral bioavailability refers specifically to the fraction of the peptide that successfully navigates the GI system and becomes biologically active at its target. Key factors influencing this include absorption, resilience, and the first-pass metabolism.

Factors Affecting Oral Peptide Bioavailability

1. Molecular Size and Structural Constraints

• Absorption Limitations: Peptides must traverse the intestinal epithelium to enter the systemic circulation. Large molecular size and complex structures often impede passage through tight junctions (passive transport) or specialized transporters (active transport).

• Electrostatic and Steric Hindrance: Electrostatic charges may repel peptides from transport apparatus, while specific three-dimensional conformations can hinder transporter binding.

• Competitive Inhibition: Other substances in the GI tract may compete for transport pathways, explaining why some medications are better absorbed under fasting conditions while others require co-administration with food.

2. Resilience in the GI Environment

The GI tract presents a hostile biochemical environment with varying pH levels:

• Stomach: pH ~1.7 (highly acidic).

• Colon: pH ~8 (alkaline).

Many peptides, optimized for the relatively stable pH of blood (~7.4), are degraded or denatured by the extreme pH fluctuations and enzymatic activity in the GI tract.

• Non-Systemic Targets: Certain peptides designed to act locally within the GI tract must still resist degradation to exert their effects.

3. First-Pass Metabolism

The hepatic portal system directs blood from the GI tract to the liver before systemic circulation. This "first-pass" allows the liver to detoxify and metabolize compounds, effectively reducing systemic bioavailability.

• Peptide Inactivation: Peptides susceptible to enzymatic degradation or structural modification by liver enzymes cannot be administered orally unless engineered to withstand these processes.

Advances in Oral Peptide Development

Despite these challenges, some peptides demonstrate oral bioavailability, primarily due to their structural or functional characteristics. Advancements in peptide engineering and delivery systems have increased the number of peptides that can be administered orally.

Examples of Orally Bioavailable Peptides

1. Structural Modifications: Modifying peptide sequences to enhance stability and absorption while reducing susceptibility to enzymatic degradation.

2. Encapsulation Techniques: Using nanoparticle-based delivery systems to shield peptides from the GI environment.

3. Selective Transport Targeting: Designing peptides to exploit specific transporters in the intestinal epithelium.