Proteins absorption barriers

Lee, V.H. 1988. Enzymatic barriers to peptide and protein absorption. Crit Rev Ther Drug Carrier Syst 5 69. 

Alveolar epithelium and local proteases are believed to be the major barriers for the efficient absorption of inhaled proteins and peptides. Many novel and potent absorption enhancers have been investigated for the peptide/protein absorption... 

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. 

Lee, V.H.L. (1987) Enzymatic barriers to peptide and protein absorption and the use of penetration enhancers to modify absorption. In Delivery systems for peptide drugs (S.S.Davis, L.Ilium and E.Tomlinson, eds). Plenum Press, New York. 

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. 

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. 

Lee VHL, Yamamoto A. Penetration and enzymatic barriers to peptide and protein absorption. Adv Drag Deliv Rev 1990 4 171-207. 

Digestive enzymes are important barriers to peptide and protein absorption [3]. They are able to digest protein drugs and include trypsin, a-chymotrypsin, elastase, and carboxypeptidase A. The first three enzymes are able to cleave internal peptide bonds in many proteins (1) trypsin has more affinity for bonds near basic amino acids, such as arginine and lysine (2) a-chymotrypsin cleaves peptide linkages near hydrophobic amino acids, such as leucine, methionine, phenylalanine, tryptophan, and tyrosine (3) elastase cleaves near alanine, glycine, isoleucine, leucine, serine, and valine. Shortly after eating, about 200-800 ig of trypsin and a-chymotrypsin are present in the human duodenum. 

One should also consider the glycocalyx, a carbohydrate-containing polymer network between the microvilli and the mucus gel coat. It probably consists mainly of oligosaccharide chains that are covalently linked to the lipids and proteins of the brush border membrane. The definite structure of the glycocalyx is not yet available, and nothing can be said about its possible importance as an absorption barrier. 

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]. 

Although iron deficiency is a common problem, about 10% of the population are genetically at risk of iron overload (hemochromatosis), and elemental iron can lead to nonen2ymic generation of free radicals. Absorption of iron is stricdy regulated. Inorganic iron is accumulated in intestinal mucosal cells bound to an intracellular protein, ferritin. Once the ferritin in the cell is saturated with iron, no more can enter. Iron can only leave the mucosal cell if there is transferrin in plasma to bind to. Once transferrin is saturated with iron, any that has accumulated in the mucosal cells will be lost when the cells are shed. As a result of this mucosal barrier, only about 10% of dietary iron is normally absorbed and only 1-5% from many plant foods. 

---