The administration of peptides plays a crucial role in the field of medicine and research. Peptides, which are short chains of amino acids, exhibit a wide range of therapeutic potential.
However, the choice of administration method varies significantly, with some peptides being administered orally, while others require parenteral routes such as injections. This distinction is driven by the concept of bioavailability, which measures how effectively a compound becomes accessible to its intended biological target.
This article delves into the factors that determine whether a peptide can be administered orally, highlighting the role of size, structure, resilience, and the first-pass effect on bioavailability.
Additionally, we explore specific examples of peptides that can be taken orally, showcasing the advancements in biochemical engineering that continue to expand the range of orally bioavailable peptides.
Bioavailability: A Key Determinant
Bioavailability is a critical factor influencing the choice of administration method for peptides. It represents the extent to which a compound becomes accessible to its intended biological destination. In the case of peptides, bioavailability indicates what proportion of the administered peptide reaches the site where it exerts its therapeutic effects. Whether a peptide can be taken orally or requires parenteral administration depends largely on its bioavailability.
Bioavailability encompasses the idea that a compound should reach its intended target, regardless of the chosen route of administration. Therefore, bioavailability applies to both injected and oral peptides. For the purposes of this article, we will specifically focus on how much of a peptide reaches its intended target after oral ingestion.
Factors Influencing Oral Peptide Bioavailability
Several factors contribute to the bioavailability of oral peptides, and these factors may either act independently or in synergy. Often, one factor dominates, significantly impacting bioavailability while overshadowing the others.
Oral Peptide Bioavailability: Size and Structure
The size and structure of peptides significantly affect their bioavailability. Peptides that are too large may struggle to fit between cells through passive transport or pass through transporters and channels via active transport in the gastrointestinal (GI) tract. Consequently, these larger peptides may simply traverse the GI system without being absorbed into the bloodstream.
Furthermore, peptides with complex 3D structures may hinder transporter binding, making absorption challenging. Electrostatic charges on some peptides may also repel transport apparatus in the GI tract. This complex interplay of factors explains why certain medications are advised to be taken with food or on an empty stomach.
Oral Peptide Bioavailability: Resilience
The resilience of a peptide to the harsh environment of the GI tract is another significant factor impacting bioavailability. The GI tract exhibits a wide range of pH values, from highly acidic (e.g., pH 1.7 in the stomach) to more neutral (e.g., pH 8 in the large intestine or colon). In contrast, blood has a relatively stable pH of about 7.4. Many peptides carried in the bloodstream may not withstand the severe conditions of the GI tract. Thus, even if they are easily absorbed, they may become damaged before reaching a site of action.
It’s important to note that not all compounds must be absorbed into the bloodstream to exert their effects. Some compounds remain in the GI tract, affecting various components of the digestive system. However, these compounds still need to be resilient to the harsh GI tract conditions to avoid degradation.
Oral Peptide Bioavailability: First-Pass Effect
The bioavailability of a peptide can also be affected by its clearance once it enters the bloodstream. Blood from the GI tract first passes through the liver before circulating throughout the rest of the body. This passage through the liver offers an opportunity for the liver to remove toxins, free radicals, and potential pathogens from the blood before they reach other, more sensitive body parts.
The liver acts as a filter, cleaning the blood. However, in its role as a filter, the liver may remove or inactivate a significant portion, or even all, of a peptide before it can reach the systemic blood supply, where it exerts its therapeutic effects. Peptides vulnerable to liver damage or removal cannot be taken orally.
Examples of Oral Peptides
Despite the challenges posed by factors such as size, structure, resilience, and the first-pass effect, some peptides can be effectively administered orally. This accomplishment is largely thanks to advancements in biochemical engineering that have allowed for the development of peptides capable of withstanding the harsh GI tract environment and achieving desirable bioavailability. Below, we explore specific examples of peptides that can be taken orally, shedding light on the innovative strategies used to enhance their bioavailability.
BPC 157, derived from a naturally occurring body protection compound, is renowned for its wound healing properties. It is effective within the GI tract and various tissues throughout the body, making it a subject of research in conditions such as Crohn’s disease, tendon and ligament injuries, burns, and more. BPC 157 possesses natural resistance to the harsh conditions of the GI tract, enabling it to exert its effects on GI conditions like inflammatory bowel disease and ulcers.
While BPC 157 is not well-absorbed by the GI tract, it is still useful in wound healing and non-GI settings. To optimize its bioavailability, scientists have developed two different forms of BPC 157. BPC 157 acetate, the first form, has a relatively long shelf life in powdered form. However, nearly 98% of it is degraded by gastric acid after a few hours, making it primarily suitable for injection. In contrast, BPC 157 arginate boasts an even longer shelf life and remains 90% bioavailable even after 5 hours in gastric acid, making it the preferred choice for oral administration. This example highlights how simple modifications can significantly alter a peptide’s bioavailability.
Ac-SDKP is a derivative of thymosin beta-4 (TB-4), a full-fledged protein consisting of 43 amino acids with a molecular weight of 4921 g/mol. Due to its large size, TB-4 cannot be absorbed by the GI tract and must be administered via injection.
However, some of TB-4’s properties are retained in shorter fragments of the protein. Ac-SDKP, composed of just four of TB-4’s amino acids, exhibits the ability to stimulate blood vessel growth and modulate inflammation. This peptide is orally bioavailable, thanks to its smaller size and its ability to withstand the acidic gastric environment. Scientists are currently exploring how Ac-SDKP may be useful in conditions such as hypertension and cardiovascular disease.
5-Amino-1MQ, a derivative of 1-methylquinolinium, plays a crucial role in regulating cellular energy expenditure. It is under investigation for its potential to promote fat loss, improve insulin and glucose levels, lower cholesterol levels, and reduce the aggressiveness of certain cancers. Remarkably, 5-amino-1MQ boasts a small molecular weight of just 159 g/mol, making it one of the smallest bioactive compounds. It is highly resistant to the stomach’s acidic environment and is readily absorbed via both passive and active transport in the GI tract, rendering it highly bioavailable when administered orally.
KPV, consisting of just three amino acids, is derived from alpha-melanocyte stimulating hormone, a much larger peptide. KPV exhibits significant anti-inflammatory effects and is currently being investigated for various applications, including inflammatory bowel disease, lung diseases, vascular conditions, and musculoskeletal disorders. It can be administered orally, intravenously, or transdermally based on the desired site of action.
Notably, while alpha-melanocyte stimulating hormone is too large for oral absorption, KPV easily traverses the GI tract via both active and passive transport while retaining some of the desirable properties of its parent peptide. This exemplifies how modifying peptides can lead to enhanced oral bioavailability.
Larazotide is a synthetic peptide derived from the toxin produced by cholera bacteria. It can modulate the permeability of the GI tract by acting on proteins called tight junctions that bind cells in the intestine to create a barrier. Larazotide, consisting of only eight amino acids, can be taken orally due to its resistance to the GI tract’s environment.
Moreover, Larazotide need not be absorbed to exert its effects. Advanced biochemistry has allowed scientists to transform a potentially deadly bacterial toxin into a beneficial peptide. Larazotide is currently undergoing clinical trials and holds promise for various GI conditions, including inflammatory bowel disease, as well as diabetes.
MK-677 mimics the effects of ghrelin and stands out as an orally bioavailable peptide. Unlike ghrelin and many other growth hormone secretagogue receptor agonists, MK-677 can be taken orally. It is currently being investigated for its potential to increase muscle mass and bone mineral density.
NMN (Nicotinamide mononucleotide)
NMN shares similarities with 5-amino-1MQ in terms of its actions. It has been shown to improve energy metabolism, enhance insulin sensitivity, and regulate plasma lipid levels. Research suggests that NMN may combat age-related weight gain. Its small size and resistance to the GI tract’s environment make it highly suitable for oral administration.
PEA, a fatty acid, has garnered attention for its potential to protect the central nervous system, reduce inflammation, and alleviate pain. As a fatty acid, PEA is readily absorbed in the GI tract and naturally resistant to degradation. It affects the endocannabinoid system and may hold promise in mitigating β-amyloid-induced neuroinflammation, as observed in Alzheimer’s disease.
While not a peptide, tesofensine is highly bioavailable when taken orally. This serotonin-noradrenaline-dopamine reuptake inhibitor, classified as a phenyltropane, was initially developed as an anti-obesity treatment. Clinical trials have demonstrated significant weight loss of up to 12.8 kg (~25 lbs) over six months. Tesofensine’s remarkable oral bioavailability can be attributed, in part, to its resistance to liver degradation. Instead, it undergoes metabolism in the kidneys after reaching the systemic circulation, exerting its effects primarily in the central nervous system.
Tributyrin, a fatty acid naturally found in butter, is an intriguing compound. Research has revealed that once absorbed, it is converted to butyric acid in the bloodstream. Butyric acid has been shown to inhibit the growth and division of cancer cells in the human colon. Tributyrin maintains stability in the GI tract and is rapidly absorbed, with its conversion to butyric acid occurring within the bloodstream. This exemplifies the concept of prodrugs, where compounds are designed to be stable in the GI tract but interact with natural enzymes in the bloodstream, creating active compounds.
Oral Peptides: A Promising Frontier
In conclusion, the ability to administer a compound orally and still achieve the desired therapeutic effects depends on several critical factors, including absorption, resilience to the GI tract environment, and evasion of liver clearance.
Advances in biochemical understanding and techniques have led to the development of orally bioavailable compounds and peptides, significantly expanding their utility in both research and clinical applications.
The examples provided in this article serve as the foundation for enhancing the oral bioavailability of various compounds.
As our understanding of biochemical processes continues to evolve, we can anticipate the emergence of novel compounds and strategies that enable more peptides and compounds, currently limited to parenteral administration, to be taken orally. This exciting frontier holds the promise of improved usability, effectiveness, and convenience, ultimately benefiting patients and researchers alike.