01dragonslayer
Administrator
Many peptides need to be administered parenterally, which is to say they need to bypass the gastrointestinal system (stomach, intestines, etc.). The most common means of parenteral administration is via injection, but there are other methods including nasal inhalation, topical creams, suppositories, eye drops, and more. But, the most convenient way to take something is by mouth – it is quick, simple, and painless. So, why is it that so many peptides need to be taken by injection? The answer comes down to bioavailability. Here is a look at why some peptides can be administered orally and what sets them apart from the peptides that need to be administered parenterally.
Of note, bioavailability is a reference to how much of a product reaches its intended target regardless of the route of administration. So, bioavailability can be defined injected peptides as well as oral peptides. For the purposes of this article, however, the term “bioavailability” will refer specifically to how much of a peptide reaches its intended target after it is taken by mouth.
The bioavailability of a peptide is dependent on several factors as discussed below. These factors may work singularly to affect bioavailability or several of them may work together. Often, one factor is dominant over the others and has such a large impact on bioavailability that the other factors can simply be ignored.
Oral Peptide Bioavailability: Size and Structure
The first factor affecting bioavailability is absorption. Peptides that are too large, for instance, may not be able to fit between cells (passive transport) or through the transporters (active transport) and channels (passive transport) in the GI tract. The result is that they simply pass through the GI system without ever be absorbed into the bloodstream. Other reasons that peptides may not be absorbed include electrostatic charges that are repelled by transport apparatus, 3D structures that make transporter binding impossible, and competition from other compounds. This latter fact is why some medications should be taken with food and some should only be taken on an empty stomach.
Oral Peptide Bioavailability: Resilience
Another factor affecting bioavailability is the resilience of a peptide to the environment in the GI tract. Measured pH values (how acidic something is) in the GI tract range from as low as 1.7 in the stomach to has high as 8 in the large intestine (colon). Blood, on the other hand, has a pH of about 7.4. Many peptides that are carried in the blood do not stand up to the harsh conditions of the GI tract. So, even though they are easily absorbed, it does not matter much because they are damaged before absorption can occur.
It is important to note here that not all compounds need to be absorbed into the bloodstream to have an effect. Some compounds remain in the GI tract and affect the stomach, small intestines, colon, etc. These compounds still need to be resilient enough to stand up to the harsh conditions in the GI tract, however, lest degradation prevent them from being useful.
Oral Peptide Bioavailability: First-Pass Effect
Finally, the bioavailability of a peptide may be affected drug clearance once it enters the bloodstream. The blood supply of the GI tract passes through the liver before it reaches the rest of the body. This gives the liver a chanced to remove toxins, free radicals, and potential pathogens before they are carried to other, more sensitive parts of the body. Think of the liver as a filter that helps to clean the blood. In its capacity as a filter, the liver may remove or inactivate most (or all) of a peptide before it can reach the systemic blood supply where it has its effect. Thus, any peptide that is subject to damage or removal by the liver cannot be taken orally.
BPC is naturally resistant to the harsh conditions of the GI tract. This allows it to have effects on GI conditions like inflammatory bowel disease and ulcers. It is not well-absorbed by the GI tract, however, so in order for it to be useful in wound healing or non-GI settings, it must be administered parenterally. This is a good example of how bioavailability can be exploited using modern biochemical engineering in order to target a specific tissue. BPC 157 taken orally has been shown, in animal studies, to promote healing in a number of gastrointestinal conditions. Alternatively, BPC 157 that is injected has an impact on tendon and ligament injuries while topical administration has an impact on dermal wounds.
Modern biochemistry can actually improve on the natural properties of BPC 157. Scientists have developed two different forms of BPC 157. BPC 157 acetate was the first form of the peptide produced. It has a relatively long shelf life in powdered form, but nearly 98% of it is degraded by gastric acid after a few hours. It is primarily used for injection for this reason. BPC 157 arginate has an even longer shelf life and is still 90% bioavailable even after 5 hours in gastric acid. It is the best option for oral administration. This is an excellent example of how simple modification can drastically alter a peptide’s bioavailability.
Some of the properties of TB-4, however, are retained in shorter fragments of the protein. Its abilities to stimulate blood vessel growth and modulate inflammation, for instance, can be achieved using just four of the forty-three amino acids in its sequence. Research shows that Ac-SDKP is orally bioavailable both as a result of its size and its ability to withstand the gastric environment. Modern biochemistry allows for the easy production of Ac-SDKP in the lab. Researchers are interested in how this peptide might be useful in hypertension and cardiovascular disease[2].
Larazotide can be taken by mouth for two reasons – it is resistant to the environment in the GI tract and it need not be absorbed to have its effect. Modern biochemistry has allowed scientists to convert a potentially deadly toxin from bacteria into a useful peptide that may be beneficial in a number gastrointestinal diseases as well as diabetes[4], [5]. Larazotide is currently undergoing clinical trials.
Whether a compound can be taken by mouth and still have an effect in the body comes down to several factors as discussed above. Advanced understanding of biochemical processes such as site of action, absorption characteristics, and more allows for the production of compounds and peptides that are orally bioavailable. As our understanding of these processes increases and natural examples of oral bioavailability are discovered, more and more compounds that can only be taken parenterally at the present will be able to be taken by mouth. This will result in improved usability of these compounds in both research and clinical settings. The above examples serve as the building blocks for scientific understanding of how to develop and enhance the oral bioavailability of a number of compounds.
Oral Peptides
Most peptides cannot be taken by mouth because little if any of the peptide would be bioavailable. Bioavailability refers to how fully a compound becomes accessible to its intended biological destination[1]. In other words, in the case of peptides, bioavailability is a measure of what proportion of a peptide gets to where it will have an effect. For example, in the case of sermorelin, bioavailability is a measure of the percent of administered sermorelin that actually reaches the growth hormone releasing hormone (GHRH) receptor.Of note, bioavailability is a reference to how much of a product reaches its intended target regardless of the route of administration. So, bioavailability can be defined injected peptides as well as oral peptides. For the purposes of this article, however, the term “bioavailability” will refer specifically to how much of a peptide reaches its intended target after it is taken by mouth.
The bioavailability of a peptide is dependent on several factors as discussed below. These factors may work singularly to affect bioavailability or several of them may work together. Often, one factor is dominant over the others and has such a large impact on bioavailability that the other factors can simply be ignored.
Oral Peptide Bioavailability: Size and Structure
The first factor affecting bioavailability is absorption. Peptides that are too large, for instance, may not be able to fit between cells (passive transport) or through the transporters (active transport) and channels (passive transport) in the GI tract. The result is that they simply pass through the GI system without ever be absorbed into the bloodstream. Other reasons that peptides may not be absorbed include electrostatic charges that are repelled by transport apparatus, 3D structures that make transporter binding impossible, and competition from other compounds. This latter fact is why some medications should be taken with food and some should only be taken on an empty stomach.
Oral Peptide Bioavailability: Resilience
Another factor affecting bioavailability is the resilience of a peptide to the environment in the GI tract. Measured pH values (how acidic something is) in the GI tract range from as low as 1.7 in the stomach to has high as 8 in the large intestine (colon). Blood, on the other hand, has a pH of about 7.4. Many peptides that are carried in the blood do not stand up to the harsh conditions of the GI tract. So, even though they are easily absorbed, it does not matter much because they are damaged before absorption can occur.
It is important to note here that not all compounds need to be absorbed into the bloodstream to have an effect. Some compounds remain in the GI tract and affect the stomach, small intestines, colon, etc. These compounds still need to be resilient enough to stand up to the harsh conditions in the GI tract, however, lest degradation prevent them from being useful.
Oral Peptide Bioavailability: First-Pass Effect
Finally, the bioavailability of a peptide may be affected drug clearance once it enters the bloodstream. The blood supply of the GI tract passes through the liver before it reaches the rest of the body. This gives the liver a chanced to remove toxins, free radicals, and potential pathogens before they are carried to other, more sensitive parts of the body. Think of the liver as a filter that helps to clean the blood. In its capacity as a filter, the liver may remove or inactivate most (or all) of a peptide before it can reach the systemic blood supply where it has its effect. Thus, any peptide that is subject to damage or removal by the liver cannot be taken orally.
Oral Peptide Examples
Of course, some peptides can be taken by mouth and there are a few reasons for that. Here is a look at some of the peptides that can be taken orally and why that is. As you will see, modern advances in biochemical engineering, particularly where peptides are concerned, continue to increase the numbers and types of peptides that can be taken by mouth.BPC 157
BPC 157 is derived from naturally occurring body protection compound. It is known for its wound healing properties both within the GI tract and throughout various tissues within the body. It has been researched in the setting of Crohn’s disease, tendon and ligament injury, burns, and more. It accelerates wound healing and reduces inflammation.BPC is naturally resistant to the harsh conditions of the GI tract. This allows it to have effects on GI conditions like inflammatory bowel disease and ulcers. It is not well-absorbed by the GI tract, however, so in order for it to be useful in wound healing or non-GI settings, it must be administered parenterally. This is a good example of how bioavailability can be exploited using modern biochemical engineering in order to target a specific tissue. BPC 157 taken orally has been shown, in animal studies, to promote healing in a number of gastrointestinal conditions. Alternatively, BPC 157 that is injected has an impact on tendon and ligament injuries while topical administration has an impact on dermal wounds.
Modern biochemistry can actually improve on the natural properties of BPC 157. Scientists have developed two different forms of BPC 157. BPC 157 acetate was the first form of the peptide produced. It has a relatively long shelf life in powdered form, but nearly 98% of it is degraded by gastric acid after a few hours. It is primarily used for injection for this reason. BPC 157 arginate has an even longer shelf life and is still 90% bioavailable even after 5 hours in gastric acid. It is the best option for oral administration. This is an excellent example of how simple modification can drastically alter a peptide’s bioavailability.
Ac-SDKP
Ac-SDKP is a derivative of thymosin beta-4 (TB-4). TB-4 is a full-fledged protein consisting of 43 amino acids with a molecular weight of 4921 g/mol. It is too large to be absorbed by the GI tract and, as such, must be administered via injection.Some of the properties of TB-4, however, are retained in shorter fragments of the protein. Its abilities to stimulate blood vessel growth and modulate inflammation, for instance, can be achieved using just four of the forty-three amino acids in its sequence. Research shows that Ac-SDKP is orally bioavailable both as a result of its size and its ability to withstand the gastric environment. Modern biochemistry allows for the easy production of Ac-SDKP in the lab. Researchers are interested in how this peptide might be useful in hypertension and cardiovascular disease[2].
5-Amino-1MQ
5-Amino-1MQ, a derivative of 1-methylquinolinium, plays important roles in regulating cellular energy expenditure. It is currently being investigated for its ability to promote fat loss, improve insulin and glucose levels, lower cholesterol levels, and reduce the aggressiveness of certain cancers. At just 159 g/mol, 5-amino-1MQ is one of the smallest bioactive compounds. It is resistant to the environment in the stomach and is readily absorbed via both passive and active transport in the GI tract. It is highly bioavailable when administered orally.KPV
KPV is just three amino acids in length. It is derived from alpha-melanocyte stimulating hormone, which is a much larger peptide. KPV has significant anti-inflammatory effects[3]. It is under investigation for in a number of settings including inflammatory bowel disease as well as diseases of the lungs, vascular system, and musculoskeletal system. It can be administered orally, intravenously, and transdermally based on the desired sight of action. While alpha-melanocyte stimulating hormone is too large to be absorbed after oral administration, KPV is easily absorbed via both active and passive transport while still retaining some of the desirable properties of alpha-melanocyte stimulating hormone.Larazotide
Larazotide is a synthetic peptide derived from the toxin that cholera bacteria produce. It can modulate the permeability of the GI tract by acting on the proteins called tight junctions that bind cells in the intestine to one another to create a barrier. Larazotide is of interest to researchers focused on Gi conditions like inflammatory bowel disease. At just eight amino acids in length, larazotide is a small peptide.Larazotide can be taken by mouth for two reasons – it is resistant to the environment in the GI tract and it need not be absorbed to have its effect. Modern biochemistry has allowed scientists to convert a potentially deadly toxin from bacteria into a useful peptide that may be beneficial in a number gastrointestinal diseases as well as diabetes[4], [5]. Larazotide is currently undergoing clinical trials.
MK-677 (Ibutamoren)
MK-677 mimics the effects of ghrelin. Unlike ghrelin and many growth hormone secretagogue receptor agonists, MK-677 can be taken by mouth. It is currently being investigated for its ability to increase muscle and bone mineral density.NMN (Nicotinamide mononucleotide)
NMN is similar to 5-amino-1MQ in its actions. It has been shown to improve energy metabolism, insulin sensitivity, and plasma lipid levels. Research reveals that it may be useful in combating age-related weight gain. Like 5-amino-1MQ, the small size and resistance of NMN to the environment of the GI tract make it ideal for oral administration.PEA (Palmitoylethanolamide)
PEA is a fatty acid that has been studied for its ability to protect the central nervous system, reduce inflammation, and combat pain. As a fatty acid, PEA is readily absorbed in the GI tract and is naturally resistant to degradation. It is known to affect the endocannabinoid system and may be useful in reducing β-amyloid-induced neuroinflammation such as is seen in Alzheimer’s disease.Tesofensine
Tesofensine is not strictly a peptide. This serotonin-noradrenaline-dopamine reuptake inhibitor is a phenyltropane. It was originally developed as a treatment for obesity and has been shown, in clinical trials, to produce weight loss of as much as 12.8 kg (~25 lbs) over six months. Tesofensine is over 90% bioavailable after oral administration, in large part because it is resistant to degradation by the liver and is instead metabolized in the kidneys after reaching the systemic circulation and having its target effects in the central nervous system.Tributyrin
Tributyrin is a fatty acid found naturally in butter. Research shows that, once absorbed, it is converted to butyric acid in the blood stream. Butyric acid has been shown to reduce the growth and division of cancer cells in the human colon. Tributryin is stable in the GI tract and rapidly absorbed while butyric acid is not. Tributyrin is an example of a prodrug. Prodrugs taken advantage of advanced understanding of biochemical processes. In this setting, a compound is created to be stable in the GI tract but then interact with natural enzymes in the bloodstream that break it apart to create an active compound.Oral Peptides: A Summary
Whether a compound can be taken by mouth and still have an effect in the body comes down to several factors as discussed above. Advanced understanding of biochemical processes such as site of action, absorption characteristics, and more allows for the production of compounds and peptides that are orally bioavailable. As our understanding of these processes increases and natural examples of oral bioavailability are discovered, more and more compounds that can only be taken parenterally at the present will be able to be taken by mouth. This will result in improved usability of these compounds in both research and clinical settings. The above examples serve as the building blocks for scientific understanding of how to develop and enhance the oral bioavailability of a number of compounds.
