Biomedical Engineering Reference
In-Depth Information
and proteins, which must first diffuse through these layers to reach the cellular mem-
brane. Due to viscosity and the interactive nature of these layers, they offer a certain
level of resistance to the protein drug diffusion. After diffusing through the mucus
and glycocalyx, the protein drug reaches the epithelial surface [53] .
10.4.2  Extracellular and Enzymatic Barriers
The GI tract has a wide variety of proteolytic enzymes, commonly considered as extra-
cellular barriers, which are involved in the degradation of peptides and proteins, mak-
ing the oral delivery of proteins and peptides a thorny issue. Various parts of the GI
tract such as the lumen, brush border, and the cytosol of the enterocytes are key loca-
tions where peptides and proteins are degraded by such proteases [54] ( Table 10.2 ).
In the GI tract, from the stomach (the first part) to the colon (the last part), families of
proteinases are ready to degrade the ingested peptides and proteins. The stomach has the
added drawback of acidic pH, from 2.0 to 3.0, as compared to other sites that have better
degradation of peptides and proteins. Such acidic environment favors the activation of
proteinases, mainly pepsins, and thereby the degradation of proteins and peptides.
Not only acidic pH but also rapid pH changes are responsible for degradation of
ingested proteins and peptides. When proteins migrate from the stomach to the duo-
denum, pH is rapidly changed from 2.0 to about 8.0. This wide pH range covers the
isoelectric points of many peptides and proteins and precipitates them. These precipi-
tated proteins do not rapidly redissolve upon pH change [55,56] .
Table 10.2 A List of Various Proteases along with Their Sites of Action
Types
Enzymes
Major Site of Action
Gastric proteases
Pepsins (aspartic proteases)
Broad activity, hydrolyze
many peptide bond peptides
Intestinal pancreatic
proteases
Trypsin (endopeptidase)
Peptide bonds of basic amino
acids/peptides
a-chymotrypsin (endopeptidase)
Peptide bonds of hydrophobic
amino acids/peptides
Elastase (endopeptidase)
Peptide bonds of smaller and
nonaromatic amino acids/
peptides
Carboxypeptidases
(exopeptidase)
A: C-terminal amino acid
B: C-terminal basic amino acid
Brush border proteases
Aminopeptidase A
Aminopeptidase N
Aminooligopeptidase
Dipeptidylaminopeptidase IV
Carboxypeptidase
Aminopeptidases are N-
terminopeptidases, degrading
mostly 3-10 amino acid
residue-dipeptides and amino
acids
Cytosolic proteases
Di- and tripeptidase
2-3 aminopeptiddamino acids
Ref. [65] . (Reprinted with permission from Taylor & Francis)
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