Peptides absorption barriers

Aungst, B. J. and H. Saitoh. Intestinal absorption barriers and transport mechanisms, including secretory transport, for a cyclic peptide, fibrinogen antagonist. Pharm. Res. 1996, 33, 114-119. 

Similarly, the 4-methoxy-2-naphthylamides of Leu, Ala, Arg, and Glu (6.1, R=side chain of amino acid, R =MeO) were used to assess the type and activity of aminopeptidase in homogenates of conjunctival, nasal, buccal, duodenal, ileal, rectal, and vaginal tissues from rabbits. This systematic comparison afforded a better understanding of the role of the aminopeptidase barrier in peptide absorption from oral vs. non-oral routes [18]. In a comparable manner, the y-glutamyltranspeptidase and dipeptidase activities were investigated in mammary tissue with the 4-nitroanilides of Leu, Met, Lys, Glu, and Asp (6.2, R=side chain of amino acid) [19]. 

Absorption barriers to peptides and proteins arise from the enzymatic barrier described above and also from the physical barrier properties of the epithelium, arising from the hydrophobic membranes and tight intercellular junctions. The physicochemical properties of peptide and protein drags generally make them unsuitable for absorption by arty of the possible routes and mechanisms described above. 

Muranishi, S., Yamamoto, A. and Okada, H. (1993) Rectal and vaginal absorption of peptides and proteins. In Biological Barriers to Protein Delivery. (Audus K.L. and Raub T.J., eds). Plenum Press, New York, pp. 199-227. Zhou, X.H. (1994) Overcoming enzymatic and absorption barrier to non-parenterally administered protein and peptide drug. J. Contr. Rel 29 239-252. 

The cellular architecture associated with each non-invasive route of administration represents a formidable physical barrier to effective absorption into systemic circulation, and the large molecular weights and relatively hydrophilic nature of proteins and peptides does not favor effective permeation. The mechanism of protein and peptide absorption has been extensively studied however, exact details about the process remain poorly understood. A general but somewhat... 

Zhou, X.H. Overcoming enzymatic and absorption barriers to non-parenterally administered protein and peptide drugs. J. Control Release 1994, 29 (3), 239-252. 

Luminal and Membrane Metabolism of Peptides and Proteins. In meaningful studies on peptide and protein drug absorption in the small intestine, it is prerequisite to distinguish among cavital, membrane contact, and intracellular drug metabolism.Cavital metabolism takes place in the lumen of the small intestine by enzymes such as trypsin, chymotrypsin, carboxypepti-dase, and elastase, which are secreted by the pancreas. Membrane contact metabolism is carried out by aminopeptidases lo-calized on the brush border membrane. Intracellular metabolism occurs inside of the cells. The known intra-celluar enzymes are cytoplasmic peptidases, prolidase, dipeptidase, and tripeptidase.A more detailed dis-cussion of this topic is presented in section Intestinal Absorption Barriers, later. 

In recent years, the successful administration of biomolecules to patients has proved to be one of the most challenging areas of the development of biopharmaceuticals, despite our knowledge of the functions of different absorption barriers in the body. This situation is reflected by the comparatively small number of biopharmaceuticals available commercially, and which are mainly administered parenteraUy, by subcutaneous or intravenous injection. Gur-rendy, depot systems to dehver peptide hormone analogs and peptide or antibody solutions and vaccines are the only marketed formulations of this type. 

A more serious problem than the physical absorption barrier, however, is that of enzymatic activity in the intestinal tract. This enzymatic barrier consists of exo- and endopeptidases and is exceptionally well designed to digest peptides and proteins. The susceptibility of peptides to enzymatic degradation is enhanced by the fact that the peptides contain several linkages, each of which may be susceptible to hydrolysis mediated by one or several peptidases. As an example, the undecapeptide substance P is susceptible to degradation by at least five different enzymes [34]. 

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