Oral Absorption of Peptides and Proteins and Their Role in Drug Pharmacokinetics

By: Taapti Rana, Saanvi Arun, Lavanya Kundurthy and Hemant N. Joshi, Tara Innovations, LLC

Editor’s Note: Hemant Joshi and his colleagues at Tara Innovations are frequent contributors to American Pharmaceutical Review and Pharmaceutical Outsourcing magazines. Tara offers internships to students interested in science. During their internship students learn how science is applied to real-world situations. American Pharmaceutical Review is proud to publish this article written by Tara’s 2026 interns.

Oral Bioavailability and the Rate of Drug Absorption

Oral bioavailability denotes the fraction of a drug taken orally that arrives in the systemic circulation as an unaltered, active form, and is capable of providing its therapeutic benefit. It is typically presented as a percentage of the amount that enters the bloodstream compared to the administered dose.¹ This metric is affected by two primary elements: the degree of drug absorption via the gastrointestinal (GI) tract and first-pass metabolism occurring in the intestinal wall and liver, where a portion of the drug might be metabolized prior to entering circulation.^{2, 3} In contrast, intravenous administration is assumed to provide a 100% bioavailability. Bioavailability is clinically crucial for establishing efficient dosing, as medications with reduced oral bioavailability might necessitate increased or more frequent doses to reach therapeutic plasma levels.¹

The rate of drug absorption, conversely, indicates how fast the active compound moves from the administration route into systemic circulation. It is assessed by the speed at which drug plasma levels increase following oral administration and is typically indicated by metrics like time to peak concentration and absorption rate constants in pharmacokinetic models.^2,3 While bioavailability emphasizes the degree of systemic availability, the absorption rate affects how quickly therapeutic levels are attained, potentially impacting the onset of drug action. Numerous physiological elements (such as gastric emptying duration, intestinal passage, solubility, and formulation properties) influence absorption rates, and variations in these can result in discrepancies in both the timing and magnitude of drug effects.³

Biopharmaceutics Classification System

The Biopharmaceutics Classification System (BCS) is a scientifically established framework used to organize orally administered drugs based on their aqueous solubility and intestinal permeability, the two main determinants of oral drug absorption and bioavailability. The system was first proposed by Amidon, Lennernäs, Shah, and Crison (1995) to provide a theoretical solution linking in vitro drug dissolution to in vivo bioavailability. Under BCS, drugs are classified into four categories. BCS Class I drugs are highly soluble and highly permeable, facilitating them to dissolve into gastrointestinal fluids and permeate the intestinal epithelium efficiently, resulting in rapid and predictable absorption. BCS Class II drugs have low solubility but high permeability, meaning that absorption is primarily limited by the rate of dissolution instead of the membrane transport. Comparatively, BCS Class III drugs possess high solubility but low permeability, so intestinal membrane transport becomes the rate-limiting step for absorption. BCS Class IV drugs demonstrate both low solubility and low permeability, so they exhibit poor, highly variable oral bioavailability and significant formulation challenges.⁴ The BCS classification has substantial regulatory and practical importance in pharmaceutical development, especially in the approval of generic drugs. Regulatory agencies such as the U.S. Food and Drug Administration use the BCS to grant biowaivers, which allow certain drug products, especially in Class I and some Class III drugs, to bypass in vivo bioequivalence studies, if they meet rigid dissolution and formulation requirements.⁵ This approach reduces the need for human testing, lowers development costs, and accelerates drug approval while maintaining safety and efficiency standards. Additionally, the BCS guides formulation scientists in choosing efficient drug delivering strategies, such as solubility enhancement techniques for Class II drugs or permeability optimization for Class III drugs.⁵

Mechanisms of Drug Absorption From Intestine

Drug absorption from the small intestine is an essential process by which drugs administered orally pass through the intestinal mucosa to enter the systemic circulation. The small intestine has a large surface and rich blood supply and is the main site of most drug absorption.² Drugs cross the intestinal epithelium by several different mechanisms, including passive diffusion, facilitated diffusion, active transport and transcellular and paracellular movements. Passive diffusion is the most common route for many drugs; it occurs when molecules move their concentration gradient down the lipid layer of intestinal epithelial cells without energy consumption. Lipid-soluble and non-ionized drugs can easily cross cell membranes via this pathway, as they can dissolve in the lipid phase of the membrane.^2,3 Facilitated diffusion involves reducing concentration gradients, but by using specific transport proteins embedded in the membrane, certain drugs can enter cells faster than simple diffusion alone, especially when they have structural similarities with endogenous substrates.² On the other hand, active transport uses energy (ATP or adenosine triphosphate) to move drugs against a concentration gradient via special transport proteins, allowing the intestinal absorption of drugs that are poorly absorbed by diffusion, especially those similar to nutrients such as amino acids or sugars.² In addition, some very hydrophilic drugs can be transported via paracellular pathway between epithelial cells, although this route is limited because narrow connections restrict access.³

Another important factor in the absorption of intestinal drugs is the presence of efflux carriers, such as P-glycoproteins, which can pump certain drugs back into the intestinal lumen, thereby reducing net absorption and reducing oral bioavailability.² The balance between the blood flow and permeability influences the amount of the drug that ultimately enters the bloodstream. Physiological conditions such as intestinal pH, intestinal transit time, movement and the presence of food or other drugs may change absorption by affecting drug dissolution and contact time with the absorption surface.³ Lipophilicity, molecular size, and ionization of drugs determine how easily a drug can penetrate the intestinal membrane.³ For example, non-ionized drugs at pH levels of the intestine are more likely to be absorbed by passive diffusion, while highly polar drugs are often based on transporter-mediated pathways.³ These mechanisms might explain why some drugs are quickly and effectively absorbed, while others are slowly or poorly absorbed, and shape their therapeutic effectiveness and dose strategies.

Details on Amino Acid and Peptide Transporters

The transporters of amino acids and peptides play an important role in the absorption of nutrients in the intestine and are also very relevant to pharmacology, as many drugs use these transport systems to enhance oral absorption. The intestinal epithelium expresses a wide variety of membrane transport proteins that mediate the absorption of amino acids and small peptides from the intestinal lumen into the enterocytes. Amino acids are primarily absorbed through sodium-dependent and sodium-independent amino acid transporters, classified based on the specificity of the substrate for neutral, acidic or basic amino acids.⁶ Sodium-dependent transporters use the electrochemical gradient of sodium ions maintained by the Na+/K+-ATPase pump to drive amino acids into the cell against their concentration gradient, which is an example of secondary active transport.⁷ This mechanism allows effective absorption even at low concentrations of luminous amino acids. On the other hand, sodium-independent transporters depend on facilitating diffusion and transporting amino acids down their concentration gradient. In addition to free amino acids, the intestine absorbs dipeptides and tripeptides efficiently through a special transporter called PEPT1 (peptide transporter 1).⁸ PEPT1 is a proton-coupled transporter that is located on the upper membrane of the enterocyte and is responsible for most of the absorption of small peptides in the intestine. Instead of sodium, PEPT1 transports peptides into cells using the protons gradient generated by light acidity. Once inside the enterocyte, these peptides are quickly hydrolyzed into individual amino acids by intracellular peptidases. PEPT1 is particularly important in drug absorption, as it can transport drugs such as peptides, including some -lactam antibiotics and angiotensin-converting enzyme (ACE) inhibitors, thus improving their oral bioavailability.⁸ This transporter displays wide substrate specificity, which clarifies why a variety of structurally different drugs can use the same uptake route.

The function and expression of amino acid and peptide transporters are affected by physiological factors like diet, developmental stage, disease conditions, and intestinal pH. For instance, diets rich in protein may increase transporter expression, improving absorptive ability.⁷ From a pharmacological viewpoint, comprehending these transporters is crucial for drug development, as focusing on amino acid or peptide transport mechanisms can greatly enhance drug absorption and therapeutic efficacy. In general, transporters for amino acids and peptides are crucial for proper human nutrition and the effective oral administration of various clinically significant medications.

Examples of Drugs Absorbed Better With Proteins/Peptides

In general, for the treatment of type-2 diabetes, the primary goal is the prevention of microvascular and macrovascular complications through achieving good glycemic control and cardiovascular risk management. Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are an effective treatment option for type-2 diabetes. These are peptide-based drugs that have been developed to activate the receptor of the gut-derived hormone GLP-1, which have an important effect on glucose homeostasis. Within the drug class, GLP-1RAs have four origins and molecular characteristics: albiglutide, dulaglutide, semaglutide, and liraglutide. Activation of GLP-1 receptors, either by native GLPs or receptor agonists, leads to insulin secretion and lowers high glucagon secretion in a glucose-dependent manner, thereby improving glycemic control. The efficacy of semaglutide was first described in a dose-response study, which confirmed the potency and duration of action. Semaglutide is fully metabolized in the human body by the same processes as other peptides and fatty acids. The bioavailability of semaglutide is relatively high (89%), with peak concentrations achieved within 1-3 days of initiation.⁹ Oral semaglutide is the first GLP-RA developed for oral administration. It received approval from the FDA in September 2019 and has since received approval from the European Medicine Agency as well. Developing GLP-1RAs to be delivered orally could potentially help aid early diabetes treatment. In addition, the simplicity of tablet administration can increase compliance. Due to the difficulty of absorption of oral semaglutide since it takes place in the stomach, an absorption enhancer known as sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC) is co-formulated along with oral semaglutide.¹⁰ On a side note, GLP-1 receptor agonists were originally developed for their use in Type 1 diabetes mellitus, but are now increasingly used for weight loss and considered as current wonder drugs.

Examples of Drugs With Reduced Absorption in the Presence of Proteins and Peptides

The drug Leoprolin Acetate (LA) is a synthetic agonist of gonadotropin-releasing hormone. It has low membrane permeability through the small intestinal tract and it is hydrolyzed by digestive enzymes. Proteins and peptides can compete with the absorption sites potentially reducing absorption of Leoprolin. The presence of high protein meals can affect the pharmacokinetics of leuprolide.¹¹

Warfarin-a drug used to prevent and treat blood clots-is an example of a drug with decreased absorption in the case of a high protein diet. High protein diets have been shown to increase serum albumin levels. This may result in more warfarin binding to serum albumin, thereby decreasing the anticoagulant effect of warfarin. The increase of albumin has been shown to occur rapidly after initiation of a high-protein diet and affects anticoagulation therapy promptly with Warfarin.¹² Protein in the diet affects vitamin K levels, which also affects Warfarin’s effectiveness.

Effects of Combination of Fats and Proteins on Drug Absorption

Oral formulations of peptide are limited by their poor stability in the formulation as well as in the GI tract and less permeability in the gastrointestinal tract (GIT). Intra or intermolecular change in the ionic concentration and extent of the hydrogen bonding capacity of protein molecules alters the three-dimensional structure of the molecule significantly. This may convert proteins from being active to essentially inactive; this then opens them up for rapid hydrolytic or enzymatic degradation. In addition, the presence of proteolytic enzymes can also rapidly degrade orally delivered protein drugs. Some examples are - endopeptidases such as trypsin, chymotrypsin, and elastase, while exopeptidases include carboxypeptidase and aminopeptidase.¹³

To solve these challenges, a lipid-based nano-carrying system can be utilized. Lipid-based nanoparticles are formulated by incorporating drug molecules into the inert lipid carriers, which are stabilized further through surfactants. This formulation is well tolerated compared to using peptides or proteins by themselves due to the use of physiological lipids such as phospholipids, cholesterols, cholesterol esters, etc. A few examples of some potential lipid-based carrier systems for controlled delivery of peptide or protein drugs include liposomes, solid lipid nanoparticles, oily suspensions, lipid microspheres, etc.¹³

Some of the advantages that lipid-based carriers offer include physiological stability and the controlled release of protein or peptide drugs because of their natural origin. Along with this, lipid-based carriers offer manufacturing simplicity, mostly through their compressibility and ease to mold. Furthermore, they are less prone to erosion and have slower water uptake which further increases protein stability.¹³

Since protein drugs are highly fragile in the GIT, lipid-based delivery systems with physical encapsulation and co-encapsulation of enzyme inhibitors reduce their degradation rate, enhance their stability, as well as their retention time significantly. Moreover, since protein drugs are less bioavailable due to their low rates of permeability, various lipid compounds have been used to reach systematic circulation through the transcellular pathway and thus increase bioavailability of these drugs.¹³

A few different types of lipid-based drug delivery systems are available. To start, one is known as solid lipid nanoparticles (SLN). The intrinsic lipoid properties of SLNs can protect the protein or peptide drugs from enzymatic degradation and control the release from the formulation. The SLN formulation strategy can increase the hydrophobicity of peptides in the method of encapsulation.

Another system is known as nano-structured lipid carriers (NLC). NLCs are colloidal carriers containing a mixture of solid and liquid lipids and having an average particle size in the nanometer range. This system is slightly better than SLN due to its ability to bypass drug expulsion during storage, elevated water content and low payload for several drugs. Additionally, self-emulsifying drug delivery systems (SEDDS) are promising lipid-based nanosized droplets typically ranging from 0-250 nm to decrease protein degradation by the GI tract fluid and also enhance protein/peptide oral absorption. In addition to this, SEDDS also increase the oral bioavailability of drugs by being thermodynamically and kinetically stable.

Furthermore, spontaneous emulsification is a type of lipid-based nanocarrier with the advantages of having a small particle size and being energy efficient. However, it should be noted that it is limited in the types of oils and emulsifiers that can be used.¹⁴

Finally, nano-capsules (NC) consist of a liquid core, normally an oil, that acts as a drug reservoir and one or more polymer coating layers encapsulating the core to control protein or peptide drug release as well as to permeate biological barriers.¹³

Future Possibilities

The low oral bioavailability, hydrophilicity, limited membrane permeability, susceptibility to enzymatic degradation, and large molecular size all pose challenges for oral delivery systems.²

One strategy for improving the proteolytic stability and membrane permeability of peptide and protein drugs includes modifying the amino acid sequence by incorporating non-natural amino acids, cyclization, D-amino acid substitution, etc. In addition, formulation strategies such as mucoadhesive systems, penetration enhancers or enteric coatings are all vital for prevention for gastric degradation of proteins and peptides.¹⁵

Enzyme inhibitors are also a promising strategy for preventing activity of intestinal enzymes such as proteolytic enzymes.¹⁵ Proteolytic enzyme inhibitors deactivate target enzymes by binding to their specific sites. A few examples of these inhibitors include aprotinin (an inhibitor of trypsin and chymotrypsin), leupeptin (inhibitor of plasmin, trypsin, papain), soybean trypsin inhibitor, and FK448 (chymotrypsin inhibitor). These can all potentially enhance the absorption of proteins and peptides through the intestinal walls. However, it should be advised that the prolonged use of these inhibitors may lead to unpredictable interactions with dietary proteins, which may cause pancreatic protease secretion and also potentially cause enzyme deficiencies.¹⁵

Another approach to enhancing absorption of proteins and peptides is using the prodrug strategy. Prodrugs are a common approach to modulate a drug’s physicochemical properties via chemical derivatization. Prodrug molecules can overcome barriers as well as convert to their active form via degradation at the desired action site. This is achieved through modifications such as esterification, bio-reversible cyclization, and lipidation. Two of the more promising strategies include bio-reversible cyclization, which includes strengthening intramolecular hydrogen bonding and minimizing interactions with water, and lipidation-enhancing hydrophobicity and intestinal permeability. However, one drawback of this approach includes binding with plasma proteins due to high lipid solubilities, thereby decreasing the concentration of free drugs in the bloodstream and interfering with specific receptor binding. Therefore, it is essential to consider the limitation of prodrugs when looking to consider their usage in pharmaceutical formulations.¹⁵

Active targeting is considered a promising approach to enhance oral absorption of peptides and proteins as well. This approach involves improving active transport by targeting receptors, transporters, and specialized cells in the intestinal epithelium. The interactions intestinal cells have with specific ligands such as vitamins and hormones can be utilized to formulate surface-functionalized nanocarriers with specific ligands that can improve targeting to specific cell populations. This in turn can facilitate more efficient absorption. Some nanocarriers are often modified with vitamins such as folic acid, biotin, or thiamine to mimic natural absorption pathways in enterocytes. Folic acid is commonly used for this and is absorbed by enterocytes through receptor-mediated endocytosis. Its biocompatibility and affinity for folic acid receptors on enterocytes make it favorable as a targeting ligand for oral nanocarriers. One drawback of this particular approach, however, includes the complexity of the nanocarrier design, as well as the need to balance biocompatibility with specificity to minimize off-target effects or limited bioavailability.¹⁵

Lipid-based nanocarriers’ potential can also be optimized by further improving the existing systems through the knowledge available. However, this is a long process and many parameters such as sufficiently high lipophilic character of HIP, stability towards lipases, mucus permeating properties and absorption enhancing properties all have to be considered when designing the formulation.¹⁴

Finally, site-specific delivery is a way to optimize the absorption of peptides and proteins in the GI tract. Specifically, this strategy focuses on the colon and the low protease activity and higher pH that the colon is composed of compared to the stomach and small intestine. One approach for delivering peptides and proteins intact to the colon is designing peptide and protein prodrugs that remain stable in other regions of the GI tract but are converted to active form in the colon. This process can be facilitated by microflora in the colon. Microflora produce reductive enzymes that are capable of cleaving specific bonds that link the prodrug to the active peptide. In addition, enzyme-controlled release mechanisms that exploit enzymatic activity of colon microflora are also considered reliable for delivering peptides and proteins to the colon. These enzymes can activate various polymeric carrier systems to protect and also release these therapeutics at the optimal absorption site. However, these systems can be significantly affected due to food or pathological conditions that can change the pH of the GI tract, which could hinder site-specific drug delivery’s effectiveness.¹⁵

Methods of current research focusing against enzymatic degradation or permeation enhancement of proteins and peptides across the intestinal membrane include platforms such as polymeric nanoparticles, self-assembling peptides, stimuli responsive hydrogels, and biomimetic systems. These systems can improve peptide stability and facilitate their passage through intestinal barriers.¹⁵

Another approach currently ongoing research includes nanotechnology combined with innovative medical devices. Microfabrication and nanofabrication techniques can create potential oral delivery devices such as microneedle patches as well as micro-containers. These help proteins and peptides bypass physiological barriers to deliver them directly to mucosal surfaces. Prototypes such as smart-ingestible devices with sensors to achieve programmable protein and peptide release at specific sites are also another interesting subject of research.¹⁵

Summary on the Roles of Proteins and Peptides on Drug Absorption

To enhance drug absorption, proteins and peptides can play a significant role. Here are some ways they contribute:

• Transport Mechanisms: Proteins can facilitate the transport of drugs across cell membranes.
• Enhanced Solubility: Peptides can improve the solubility of poorly soluble drugs, aiding absorption.
• Targeted Delivery: Certain peptides can target specific tissues, increasing drug efficacy.
• Formulation Additives: Proteins can be used as excipients in drug formulations to enhance stability and absorption.
• Mucosal Penetration: Some peptides can enhance drug penetration through mucosal barriers, like the intestinal lining.
• Bioavailability Improvement: Using peptides can increase the bioavailability of therapeutic agents by protecting them from degradation.

Examples of drugs getting help from proteins and peptides

• Insulin: Co-administered with peptides to improve absorption in diabetic patients.
• Calcitonin: Peptide coadministration enhances its bioavailability for osteoporosis treatment.
• Glucagon-like peptide-1 (GLP-1) agonists: Used with oral medications to improve glucose control in diabetes.
• Peptide-based vaccines: Proteins can enhance the immune response and absorption of vaccine components.
• Cyclosporine: Co-administered with absorption enhancers to improve bioavailability in transplant patients.
• Antibiotics: Certain peptides can increase the absorption of oral antibiotics in the gastrointestinal tract.

Conclusion

Overall, the research and development of oral proteins and peptides needs to be further developed as a handful of challenges exist for successful clinical trials. Also, each protein or peptide has unique properties and they must be evaluated individually. However, a lot of successful prospective ideas need further research. For example, combining fats and proteins through lipid-based nanocarriers should be explored further, as there is promising potential to have high oral bioavailability. Additionally, prospective ideas such as modifying the amino acid sequence, enzyme inhibitors, prodrug strategies, active targeting, and site-specific delivery should also be further researched to increase effectiveness.

Proteins and peptides play a significant role in the pharmacokinetics of various drugs. More research should be conducted to evaluate possibilities.

References

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