Oral Delivery of Proteins and Peptides: Concepts and Applications - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 483

Luminal and Membrane Metabolism of Peptides and Proteins
When peptides and proteins are administered through the oral route, they tend to
metabolize at three major sites before reaching the blood: in the lumen, on the sur-
face of the membrane, and within the cell context. In the intestinal lumen, various
enzymes, such as trypsin, chymotrypsin, carboxypeptidase, and elastase, are secreted
by the pancreas, which metabolizes peptides and proteins [33] . On the surface of
the membrane, the metabolism of peptides and proteins is caused by the presence of
various aminopeptidases located on the brush border. Prolidase, dipeptidase, tripep-
tidase, and cytoplasmic peptidases are present within the cell and are responsible for
intracellular metabolism of administered peptides and proteins [29] .
10.2.2.3 Large Intestine (Colon)
The large intestine is a tubelike structure having approximately 60 in. length and 2 in.
diameter. It is further subdivided into the cecum, which is the beginning, or opening,
of the colon; the ascending colon; the transverse colon; the descending colon, and the
sigmoid colon, which continues into the rectum. As in the small intestine, the wall of
the large intestine is also divided into four layers: the serosa, the muscularis externa,
the submucosa, and the mucosa. These tissue layers are depicted in Fig. 10.1 . In the
large intestine, villi, microvilli, and crypts are not present, and hence it offers much
less surface area for the absorption of administered peptides and proteins. The cells
are much less dense than those in the small intestine. A large amount of various bac-
teria are present in the large intestine, whereas there is much less of a bacterial load
in the small intestine and stomach. These bacteria are involved in the digestion of
residual food into caloric substance for absorption. Colon targeting is achieved by
delivering peptide and protein drugs coated with polymers that are only degraded by
azoreductases released by colonic bacteria [13] . Because of low enzymatic activity in
the colon, colon targeting has gained much attention for the delivery of peptide and
protein drugs. Table 10.1 describes anatomical and physiological properties of each
absorption area of the GI tract [35] .
10.3 Transport Mechanisms in the GI Tract
There are four distinct mechanisms for molecules to cross the membrane: via para-
cellular, transcellular, carrier-mediated, and receptor-mediated transport ( Fig. 10.3 ).
10.3.1 Paracellular Transport
Drug molecules pass through aqueous pores created by epithelial tight junctions.
This is the most likely route for polar, hydrophilic drugs because they exhibit poor
membrane partitioning. Peptides are presumed to permeate through the aqueous
pathways, in other words, the paracellular and aqueous pore paths. In the human
small intestine, the average size of these water-filled pores is approximately 7-9 Å
for the jejunum, 3-4 Å for the ileum, and 8-9 Å for the colon [36,37] . The extent of