Improvement of oral peptide bioavailability: Peptidomimetics and prodrug strategies
Introduction
Recent dramatic advances in recombinant DNA technology and modern synthetic methodologies allow for the production of large quantities of structurally diverse peptides possessing a broad spectrum of pharmacological effects. The clinical development of these potential drugs, however, has been restricted due to their very poor permeation across biological barriers (e.g., intestinal mucosa) and their rapid metabolism. These characteristics generally lead to low oral bioavailabilities (<1–2%) and short in vivo half-lives (<30 min) 1, 2, 3, 4, 5, 6, 7.
The successful design of peptide-based drugs with acceptable oral bioavailabilities will be a major challenge confronting pharmaceutical scientists in the future. The design of orally bioavailable peptide-based drugs will necessitate a compromise between incorporation of those structural features that optimize the pharmacological properties (e.g., receptor binding) and those structural features that optimize the biopharmaceutical properties (e.g., membrane permeability, clearance, metabolism) of the molecule. Alternatively, transient modifications of the pharmaceutical and/or biopharmaceutical properties of the molecule using prodrug strategies will be necessary.
The major biological barriers to the oral delivery of peptide-based drugs include the intestinal lumen, intestinal mucosa and the liver. This review will focus on the barrier properties of the intestinal lumen and mucosa and on chemical strategies (e.g., peptidomimetics and prodrugs) that are used to circumvent these biological barriers. This review will not cover the role of the liver in limiting oral bioavailability of peptide-based drugs since this subject has been recently reviewed in depth 8, 9, 10. In addition, this review will not cover formulation strategies used to enhance oral bioavailability of peptide-based drugs since this subject has also recently been reviewed extensively [11].
Section snippets
Intestinal lumen
Physiologically, the gastrointestinal tract is designed to break down dietary proteins into subunits that are sufficiently small (e.g., di/tripeptides, amino acids) to be absorbed across the intestinal mucosa [12]. Digestive processes for proteins and peptides are catalyzed by a variety of enzymes that are specialized in the hydrolysis of peptide bonds. Due to the wide substrate specificity of these proteases and peptidases, it is not surprising that the metabolic activity in the intestinal
Preventing metabolism
An orally delivered peptide encounters proteolytic enzymes at many points, from pancreatic endopeptidases present in the gastrointestinal lumen (e.g., chymotrypsin, trypsin and elastase) and extending to other proteases that are present in the intestinal mucosa (see Section 2.1and Section 2.2), as well as in the liver, kidney and other organs. Side chain metabolism may also be important and tends to mirror the chemistry associated with the functional group being considered. Side chain reactions
Conclusions
Through structural modification of peptides to form peptidomimetics, medicinal chemists have successfully circumvented the metabolic enzymes present in the intestinal mucosa. However, metabolism is not the only factor that limits the permeation of peptides across the cellular intestinal barrier. Because of the hydrophilic nature of most natural peptides, their fluxes across this cell monolayer are generally restricted to the paracellular route. Peptides restricted to this pathway generally have
Acknowledgements
The authors' research in this area has been supported by research grants from the United States Public Health Services (DA-09315, GM-51633, GM-088359), Glaxo–Wellcome, Inc., Costar Corporation, Japan Tabacco, Inc., SmithKline Beecham Corp., and the Swiss National Science Foundation.
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