Enzymatic barrier

Possible noninvasive routes for delivery of proteins include nasal, buccal, rectal, vaginal, transdermal, ocular, oral, and pulmonary. For each route of delivery there are two potential barriers to absorption permeability and enzymatic barriers. All of the... 

Proteolytic enzymes in the respiratory mucosa play important role(s) in the regulation of lung inflammation and remodelling [123, 124], Pulmonary proteolytic enzymes, however, also comprise one of the barriers which pulmonary-administered protein/peptide drugs have to overcome in order to achieve adequate bioavailability [125]. Intriguingly, the pulmonary enzymatic barrier is an aspect that has been little investigated and is poorly understood. Inconsistencies in the data available to date are most likely a result of the use of different techniques (e.g., PCR, immunotechniques and enzyme activity assays), different species and different cell (pheno)types, for example primary cells vs. cell lines. 

Drug molecules that have traversed the physieal and enzymatic barriers of the colonic mucosa may enter the blood-eapillary bed or the lymphatic sinuses. Intact drug that reaches the venous capillaries from the submucosa is transported to the liver via the hepatic-portal system where they may undergo significant metabolism. On the other hand, uptake into the lymphatie sinuses of the colon results in direct delivery into the systemic circulation that causes less metabolic breakdown of the absorbed drug [3]. 

Bernkop-Schnurch, A., The use of inhibitory agents to overcome the enzymatic barrier to perorally administered therapeutic peptides and proteins, J. Control. Rel., 52 1-16 (1998). 

Woodley, J.F., Enzymatic barriers for GI peptide and protein delivery. Crit Rev Ther Drug Carrier Syst, 1994.11(2-3) 61-95. 

Unfortunately, bacitracin causes nephrotoxicity [36] and so its use as a suitable adjuvant to overcome the enzymatic barrier is quite questionable. Interestingly, it was demonstrated recently that bacitracin, when covalently linked to a mucoadhesive polymer, still displays its inhibitory activity [30]. The immobilization to an unabsorbable drug carrier matrix is believed to lead to an exclusion of systemic toxic side effects, but detailed toxicological studies are necessary to prove this hypothesis. 

As mentioned above, the rectal route is very attractive for systemic delivery of peptide and protein drugs, but rectal administration of peptides often results in very low bioavailability due to not only poor membrane penetration characteristics (transport barrier) but also due to hydrolysis of peptides by digestive enzymes of the GI tract (enzymatic barrier). Of these two barriers, the latter is of greater importance for certain unstable small peptides, as these peptides, unless they have been degraded by various proteases, can be transported across the intestinal membrane. Therefore, the use of protease inhibitors is one of the most promising approaches to overcome the delivery problems of these peptides and proteins. Many compounds have been used as protease inhibitors for improving the stability of various peptides and proteins. These include aprotinin, trypsin inhibitors, bacitracin, puromycin, bestatin, and bile salts such as NaCC and are frequently used with absorption enhancers for improvement in rectal absorption. 

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

Overcoming enzymatic barriers, particularly for peptide and protein drugs... 

Abstract The major enzymatic barrier to the absorption of macromolecules, particularly therapeutic peptides, is the pancreatic enzymes the peptidases, nucleases, lipases and esterases that are secreted in considerable quantities into the intestinal lumen and rapidly hydrolyse macromolecules and lipids. In the case of the peptidases, they work in a co-ordinated fashion, whereby the action of the pancreatic enzymes is augmented by those in the brush borders of the intestinal cells. The sloughing-off of mucosal cells into the lumen also furnishes a mixture of enzymes that are a threat to macromolecules. As the specificity and activity of the enzymes are not always predictable, during pharmaceutical development it is important to test the stability of therapeutic macromolecules, and novel macromolecular-containing or lipid-containing formulations, in the presence of mixtures of pancreatic enzymes and bile salts, or in animal intestinal washouts or ideally, aspirates of human intestinal contents. 

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