Improvement of oral peptide bioavailability: Peptidomimetics and prodrug strategies

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Abstract

Clinical development of orally active peptide drugs has been restricted by their unfavorable physicochemical properties, which limit their intestinal mucosal permeation and their lack of stability against enzymatic degradation. Successful oral delivery of peptides will depend, therefore, on strategies designed to alter the physicochemical characteristics of these potential drugs, without changing their biological activity, in order to overcome the physical and biochemical barrier properties of the intestinal cells. This manuscript will focus on the physiological limitations for oral peptide delivery and on various strategies using chemical modifications to improve oral bioavailability of peptide-based drugs.

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.

References (209)

  • I. Ojima et al.

    Antithrombic agents: from RGD to peptide mimetics

    Bioorg. Med. Chem.

    (1995)
  • J. Boger

    Renin inhibitors

    Annu. Rep. Med. Chem.

    (1985)
  • S. Lundin et al.

    Absorption of a vasopressin analogue, 1-deamino-8-d-arginine-vasopressin (dDAVP), in a human intestinal epithelial cell line, Caco-2

    Int. J. Pharm.

    (1990)
  • A. Adson et al.

    Quantitative approaches to delineate paracellular diffusion in cultured epithelial cell monolayers

    J. Pharm. Sci.

    (1994)
  • N.F.H. Ho et al.

    Biophysical model approaches to mechanistic transepithelial studies of peptides

    J. Control. Release

    (1990)
  • P.F. Augustijns et al.

    Evidence for a polarized efflux system in Caco-2 cells capable of modulating cyclosporin A transport

    Biochem. Biophys. Res. Commun.

    (1993)
  • C. McMartin et al.

    Analysis of structural requirements for the absorption of drugs and macromolecules from the nasal cavity

    J. Pharm. Sci.

    (1987)
  • J. Hochman et al.

    Mechanisms of absorption enhancement and tight junction regulation

    J. Control. Release

    (1994)
  • R.N. Smith et al.

    Selection of a reference partitioning system for drug design work

    J. Pharm. Sci.

    (1975)
  • M.A. Roseman

    Hydrophobicity of the peptide C=O–H-N hydrogen-bonded group

    J. Membr. Biol.

    (1988)
  • W.A. Banks et al.

    Entry of DSIP peptides into dog CSF: Role of physicochemical and pharmacokinetic parameters

    Brain Res. Bull.

    (1986)
  • M.J. Humphrey et al.

    Peptides and related drugs: a review of their absorption, metabolism and excretion

    Drug Metab. Rev.

    (1986)
  • V.H.L. Lee et al.

    Penetration and enzymatic barriers to peptide and protein absorption

    Adv. Drug Deliv. Rev.

    (1990)
  • V. Bocci

    Catabolism of therapeutic proteins and peptides with implications for drug delivery

    Adv. Drug Deliv. Rev.

    (1990)
  • X.H. Zhou

    Overcoming enzymatic and absorption barriers to non-parenterally administered protein and peptide drugs

    J. Control. Release

    (1994)
  • G.L. Amidon et al.

    Absorption of peptide and peptidomimetic drugs

    Ann. Rev. Pharmacol. Toxicol.

    (1994)
  • D.K.F. Meijer, K. Ziegler, Mechanisms for the hepatic clearance of oligopeptides and proteins: Implications for rate of...
  • D.L. Marks, G.J. Gores, N.F. LaRusso, Hepatic processing of peptides, in: M.D. Taylor, G.L. Amidon (Eds.),...
  • M.J. Ruwart, Approaches to modulating liver transport of peptide drugs. in: M.D. Taylor, G.L. Amidon (Eds.),...
  • J.L. Cleland, R. Langer (Eds.), Formulation and Delivery of Proteins and Peptides, American Chemical Society,...
  • D.H. Alpers, Digestion and absorption of carbohydrates and proteins, in: L.R. Johnson (Ed.), Physiology of the...
  • D.M. Matthews

    Intestinal absorption of peptides

    Physiol. Rev.

    (1975)
  • S.A. Adibi, Y.S. Kim, Peptide absorption and hydrolysis, in: L.R. Johnson (Ed.), Physiology of the Gastrointestinal...
  • V.H.L. Lee, R.D. Traver, M.E. Taub, Enzymatic barriers to peptide and protein drug delivery, in: V.H.L. Lee (Ed.),...
  • R.H. Erickson, Peptide metabolism at brush-border membranes, in: M.D. Taylor, G.L. Amidon (Eds.), Peptide-Based Drug...
  • R. Krishnamoorthy, A.K. Mitra, Peptide metabolism by gastric, pancreatic and lysosomal proteinases, in: M.D. Taylor,...
  • S.A. Adibi

    Intestinal transport of dipeptides in man: relative importance of hydrolysis and intact absorption

    J. Clin. Invest.

    (1971)
  • M. Cereijido, O. Ruiz, L. González-Mariscal, R.G. Contreras, M.S. Balda, M.R. Garcı́a-Villegas, The paracellular...
  • M. Cereijido et al.

    Occluding junctions in cultured epithelial monolayers

    Am. J. Physiol.

    (1981)
  • J.L. Madara et al.

    Occluding junction structure–function relationships in a cultured epithelial monolayer

    J. Cell Biol.

    (1985)
  • R.A. Conradi, P.S. Burton, R.T. Borchardt, Physico-chemical and biological factors that influence a drug's cellular...
  • K. Siminoski et al.

    Uptake and transepithelial transport of nerve growth factor in suckling rat ileum

    J. Cell Biol.

    (1986)
  • G.J. Strous et al.

    Mucin-type glycoproteins

    Crit. Rev. Biochem. Mol. Biol.

    (1992)
  • Y.S. Kim et al.

    Peptide hydrolases in the brush-border and soluble fractions of small intestinal mucosa of rat and man

    J. Clin. Invest.

    (1972)
  • A.J. Barrett, J.K. McDonald, Mammalian Proteases: a Glossary and Bibliography, Vol. 1, Endopeptidases, Academic Press,...
  • J.K. McDonald, A.J. Barrett, Mammalian Proteases: a Glossary and Bibliography, Vol. 2, Exopeptidases, Academic Press,...
  • J.P.F. Bai

    Comparison of distribution of brush-border exo- and endopeptidases in rat and rabbit intestine

    J. Pharm. Pharmacol.

    (1994)
  • G.J. Leitch

    Regional variations in the composition of purified brush-borders isolated from infant and adult rabbit small intestine

    Arch. Int. Physiol. Biochem.

    (1971)
  • T. Lindberg

    Intestinal dipeptidases: dipeptidase activity in the mucosa of the gastrointestinal tract of the adult human

    Acta Physiol. Scand.

    (1966)
  • E.E. Sterchi

    The distribution of brush-border peptidases along the small intestine of the adult human

    Pediatr. Res.

    (1981)
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