Peptides are crucial molecules in numerous biological processes, but their administration has long posed challenges, especially via the oral route. This article delves into the complexities of oral peptide bioavailability, exploring various factors that influence it and highlighting examples of peptides that have successfully overcome these hurdles. As an experienced peptide researcher, this review aims to provide an informative perspective on the current state of research in this field.
Understanding Bioavailability
Bioavailability refers to the proportion of a compound that reaches its intended biological destination. In the context of peptides, it measures the percentage of an administered peptide that reaches its target, such as the growth hormone-releasing hormone (GHRH) receptor for sermorelin. Bioavailability can be defined for any route of administration, but this article focuses on oral bioavailability.
Several factors influence the bioavailability of peptides when taken orally. These factors can work individually or synergistically, with one often dominating the others. Understanding these factors is crucial for improving peptide delivery and efficacy.
Factors Affecting Oral Peptide Bioavailability
Absorption: Size and Structure
The first factor affecting bioavailability is absorption. Peptides that are too large may not fit between cells (passive transport) or through transporters (active transport) and channels in the gastrointestinal (GI) tract. This results in their passage through the GI system without absorption into the bloodstream. Other reasons for poor absorption include electrostatic charges that repel transport apparatus, three-dimensional structures that prevent transporter binding, and competition from other compounds.
Resilience to the GI Environment
Another critical factor is the peptide’s resilience to the GI environment. The GI tract has varying pH levels, from as low as 1.7 in the stomach to as high as 8 in the large intestine. Many peptides that are stable in the blood (pH 7.4) degrade in these harsh conditions before absorption can occur. Peptides intended to affect the GI tract directly must also withstand these conditions to be effective.
First-Pass Effect
Once a peptide enters the bloodstream from the GI tract, it passes through the liver, which can remove or inactivate most or all of it before it reaches the systemic circulation. This “first-pass effect” is a significant barrier to oral peptide administration. Peptides subject to significant liver degradation cannot be effectively administered orally.
Examples of Oral Peptides
Despite these challenges, several peptides have been developed that can be taken orally. Here are some notable examples and the reasons for their success:
BPC 157
BPC 157 is derived from a naturally occurring body protection compound and is known for its wound healing properties. It is resistant to the harsh conditions of the GI tract, making it effective for conditions like inflammatory bowel disease and ulcers. However, it is not well absorbed, so it must be administered parenterally for systemic effects. Modern biochemistry has improved BPC 157’s properties, creating forms like BPC 157 arginate, which is 90% bioavailable even after five hours in gastric acid.
Ac-SDKP
Ac-SDKP is a derivative of thymosin beta-4 (TB-4) and retains some of its properties, such as stimulating blood vessel growth and modulating inflammation. At just four amino acids long, Ac-SDKP is small enough to be absorbed in the GI tract and withstand the gastric environment. This makes it a promising candidate for treating hypertension and cardiovascular disease.
5-Amino-1MQ
5-Amino-1MQ is a derivative of 1-methylquinolinium and regulates cellular energy expenditure. It is resistant to stomach conditions and readily absorbed via passive and active transport in the GI tract. Its small size and resilience make it highly bioavailable orally, and it is being investigated for fat loss, improved insulin and glucose levels, and cancer treatment.
KPV
KPV is a tripeptide derived from alpha-melanocyte stimulating hormone and has significant anti-inflammatory effects. It is under investigation for various conditions, including inflammatory bowel disease and diseases of the lungs, vascular system, and musculoskeletal system. KPV is easily absorbed via both active and passive transport, retaining desirable properties of its parent hormone while being orally bioavailable.
Larazotide
Larazotide is a synthetic peptide derived from cholera toxin, modulating the permeability of the GI tract by acting on tight junctions between intestinal cells. It is resistant to GI conditions and does not need to be absorbed to exert its effects. Larazotide is being studied for its potential in treating GI conditions like inflammatory bowel disease and diabetes.
MK-677 (Ibutamoren)
MK-677, which mimics ghrelin, can be taken orally unlike ghrelin itself. It is currently being investigated for its ability to increase muscle and bone mineral density.
NMN (Nicotinamide Mononucleotide)
NMN improves energy metabolism, insulin sensitivity, and plasma lipid levels. Its small size and resilience to GI conditions make it ideal for oral administration, showing promise in combating age-related weight gain.
PEA (Palmitoylethanolamide)
PEA is a fatty acid known for protecting the central nervous system, reducing inflammation, and combating pain. It is readily absorbed in the GI tract and naturally resistant to degradation, making it effective in oral formulations.
Tesofensine
Tesofensine is a serotonin-noradrenaline-dopamine reuptake inhibitor developed for treating obesity. It is over 90% bioavailable after oral administration and has shown significant weight loss effects in clinical trials.
Tributyrin
Tributyrin is a fatty acid found in butter, converted to butyric acid in the bloodstream. Butyric acid reduces the growth of cancer cells in the colon. Tributyrin’s stability in the GI tract and rapid absorption make it a promising prodrug.
Summary
The ability of a compound to be taken orally and have an effect in the body depends on several factors, including absorption, resilience to GI conditions, and the first-pass effect. Advances in biochemistry and a deeper understanding of these processes have led to the development of peptides that are orally bioavailable. As research progresses, more compounds currently limited to parenteral administration may become orally viable, improving their usability in both research and clinical settings.
By understanding and leveraging the factors influencing oral bioavailability, scientists can continue to expand the possibilities for peptide-based therapies and research, ultimately enhancing the effectiveness and accessibility of these important compounds.