Natural Oral Absorption of Therapeutic Peptides: Mechanisms and Physiological Determinants.

Although oral peptide drug administration is the most desirable for both patients and healthcare systems, it is a major pharmaceutical challenge. Typically, less than 1% of orally administered peptide therapeutics reaches the systemic circulation. Modern research has focused on overcoming the physiological barriers responsible for the poor peptide drug bioavailability, while little attention has been given to understanding how measurable absorption occurs despite the barriers. This review aimed to explore the physiological factors that influence oral peptide absorption, such as enzymatic degradation and pH effects, motility, microbiota, transporters, tight junctions, and the effect of inflammation. The available data indicate that these factors function not only as barriers but may also create limited opportunities for peptide uptake. Enzymatic degradation and microbial metabolism reduce the availability of intact peptide drugs yet may generate biologically relevant fragments. Tight junctions are generally regarded as restrictive barriers but are shown to exhibit dynamic regulations that may permit transient paracellular transport. Similarly, gastrointestinal motility, microbiota, and inflammatory processes influence epithelial permeability and duration of peptide exposure both to absorptive surfaces and to degradative enzymes. In contrast, transporter-mediated uptake appears unlikely to account for the absorption of intact peptide drugs due to their substrate size limitations. Together, the findings suggest that measurable oral peptide absorption is unlikely to result from a single dominant pathway but rather from the cumulative contribution of the mechanisms. Improved understanding of these endogenous mechanisms may open opportunities to enhance oral peptide bioavailability and support the development of more effective therapeutics.