Proteomics - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 402

gradient utilizing the energy generated by adenosine triphosphate (ATP).
Polypeptides and proteins mainly follow endocytosis, which is subdivided into pino-
cytosis (fluid phase), receptor-mediated endocytosis, and transcytosis.
However, transcellular transport is not as simple as it apparently seems to be so.
P-glycoprotein, a 170-kDa protein, acts as an efflux pump that acts in reverse to
transcellular drug absorption. P-glycoprotein is found in the epithelial cells of the
kidney, liver, and gastrointestinal tract.
8.4.5 Role of Bile Acid Transporters
The role of the mucus layer in the elucidation of penetration enhancement has been
highly overlooked, as their role in absorption of peptides is not fully understood.
Much less information is available on the effect of enhancers on the structure and
viscosity of mucus. For instance, bile salts like sodium deoxycholate, sodium tauro-
deoxycholate, sodium glycocholate, and lysophosphatidylcholine have been found to
reduce viscosity and flexibility of bronchial mucosa and thereby facilitate enhanced
penetration of proteins and peptides intended for therapeutic action in lungs and
bronchi subsequently. Bile salts and acid usually improve penetration by chelating
action. Examples of other permeation enhancers with similar mechanisms of action
include N -acylcollagen peptides and saponins.
Many investigators have described the use of several classes of compounds as
absorption enhancers for proteins and peptides. This class consists of surfactants, bile
acids, saponins, phospholipids, organic alcohols, amines, fats, and salts. Conjugated
bile salts have been found to significantly increase solubilization of cyclosporine and
thereby its oral bioavailability [34] .
Bile salts have been found to significantly alter the absorption rate of drugs from
intestinal parts. The absorbing capacity of the small intestine decreases in descending
order from the duodenum to the ileum. A specialized transport mechanism exists in
the ileum to absorb bile acids. One of the prerequisites for bile acids for active
transport is an acidic side chain at the 17th position of the ring; C3 derivatives may
undergo active transport. Ho [35] reported increased absorption of p -toluenesulfonic
acid from the ileum following conjugation with cholic acid.
Sodium glycocholate was found to be effective in enhancing buccal absorption
of insulin in beagle dogs to some extent. Significant improvement in absorption was
also seen with a vasodilator. Nakada [36] observed enhanced buccal absorption of
calcitonin in human subjects in the presence of bile salts and acids. The study was
conducted using bile acids, sodium lauryl sulfate, and sodium myristate and sugar
esters. Ichikawa [37] studied the effects of a variety of surfactants, phospholipids in
combination with bile salts.
However, there are three other safety concerns associated with the use of penetra-
tion enhancers, which require proper attention. One of the most serious is that they
interfere with normal metabolism and physiological processes. For instance, perfu-
sion of hamster jejunum with conjugated and unconjugated bile acids results in the
inhibition of water absorption. Vital processes like glucose and amino acid absorption
are also blocked by unconjugated bile acids, which may prove fatal for an organism.