Biopharmaceutics of transmucosal peptide and protein drug administration: role of transport mechanisms with a focus on the involvement of PepT1

doi:10.1016/S0168-3659(99)00030-9

Journal of Controlled Release

Volume 62, Issues 1–2, 1 November 1999, Pages 129-140

https://doi.org/10.1016/S0168-3659(99)00030-9 Get rights and content

Abstract

Non-invasive delivery of peptide and protein drugs will soon become a reality. This is due partly to a better understanding of the endogenous transport mechanisms, including paracellular transport, endocytosis, and carrier-mediated transport of mucosal routes of peptide and protein drug administration. This paper focuses on work related to the elucidation of structure-function, intracellular trafficking, and regulation of the intestinal dipeptide transporter, PepT1.

Section snippets

Paracellular transport

During the past 3 years, chitosans of varying degrees of acetylation and molecular weight have been investigated as potential penetration enhancers [1], [2], [3], [4], [5], [6]. The efficacy and toxicity of these polycationic polymers are a function of their degree of acetylation and molecular weight [6], [7]. A parallel development is the discovery of a pentapeptide called Pz-peptide (4-phenylazobenzoxycarbonyl-Pro-Leu-Gly-Pro-d-Arg, Mw 777), that instinctively seeks out the paracellular

Endocytosis

On the endocytosis front, there is a better appreciation for its utility in mediating protein absorption outside of the gastrointestinal tract. The alveolar epithelium of the lungs is an example of such an absorption site with the capacity for endocytosis. The associated permeability coefficient (Papp) for macromolecules that rely on endocytosis for transport is, however, two- to four-orders of magnitude smaller. Nevertheless, provided that at least 10% of the alveolar surface area is available

Carrier-mediated transport: the role of PepT1

Perhaps the most exciting development in transmucosal peptide and protein drug delivery during the past 5 years is the cloning of the intestinal dipeptide transporter PepT1 [17], [18], [19], [20], a 707 amino acid, 12-transmembrane domain, proton-coupled transporter protein that plays an important role in the transport of nutritional di- and tripeptides as well as peptidomimetics such as penicillins, cephalosporins, and angiotensin-converting enzyme inhibitors [18], [21], [22], [23], [24], [25]

Summary

We have described an approach to study the structural, cellular, and environmental factors that may affect the activity of PepT1. The cornerstone of such an approach is a systematic computer modeling approach that attempts to define the chemical and spatial properties of the key amino acids involved in substrate binding and translocation via PepT1. Thus, computer modeling suggests a list of possible amino acid residues key to transporter function for verification by site-directed mutagenesis

Acknowledgements

Some of the work described herein was supported in part by NIH grants DK51588 (CTO) and GM52812 (VHLL).

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¹: Current address: Uppsala University, Department of Pharmaceutics, P.O. Box BMC, Uppsala, Sweden S-75123.

²: Current address: Advanced Inhalation Research, Inc., 840 Memorial Drive, Cambridge, MA 02139, USA.

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Biopharmaceutics of transmucosal peptide and protein drug administration: role of transport mechanisms with a focus on the involvement of PepT1

Abstract

Section snippets

Paracellular transport

Endocytosis

Carrier-mediated transport: the role of PepT1

Summary

Acknowledgements

Eur. J. Pharm. Sci.

J. Control. Rel.

J. Control. Rel.

J. Control. Rel.

Eur. J. Pharm. Sci.

J. Biol. Chem.

Biochim. Biophys. Acta

Life Sci.

Int. J. Pharm.

J. Biol. Chem.

Biochim. Biophys. Acta

FFBS Lett.

Biochem. Biophys. Res. Comm.

J. Pharm. Sci.

J. Mol. Biol.

J. Control. Rel.

J. Biol. Chem.

Biochim. Biophys. Acta

Biochim. Biophys. Acta

Biochim. Biophys. Acta

Biophys. J.

J. Mol. Graphics

J. Biol. Chem.

J. Biol. Chem.

Eur. J. Pharmacol.

Biochim. Biophys. Acta

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Effect of chitosan on the permeability of monolayers of intestinal epithelial cells (Caco-2)

Pharm. Res.

Chitosan as a novel nasal delivery system for peptide drugs

Pharm. Res.

Chitosans as absorption enhancers for poorly absorbable drugs. I. Influence of molecular weight and degree of acetylation on drug transport across human intestinal epithelial (Caco-2) cells

Pharm. Res.

Chitosans as absorption enhancers for poorly absorbable drugs 2: Mechanism of absorption enhancement

Pharm. Res.

N-trimethyl chitosan chloride as a potential absorption enhancer across mucosal surfaces: In vitro evaluation in intestinal epithelial cells (Caco-2)

Pharm. Res.