Peptide transporters routes

Shi, B., Song, D., Xue, H., Li, J. and Li, N. (2006) Abnormal expression of the peptide transporter PepTl in the colon of massive bowel resection rat a potential route for colonic mucosa damage by transport of fMLP. Digestive Diseases and Sciences, 51 (11), 2087-2093. 

In spite of the obstacles to oral delivery, substantial evidence suggests that pharmaceutical polypeptides are absorbed through the intestinal mucosa, although in minute amounts.10 Small amounts of polypeptide drugs can be absorbed by the action of specific peptide transporters in the intestinal mucosa cells.11 This suggests that properly formulated proteins or peptide drugs may be administered by the oral route with retention of sufficient biological activity for their therapeutic use. 

A major difference between the classical transmitters and peptides is that the production of a peptide is quite different since the synthesis of a peptide is in the form of a huge precursor of about 300 amino acids which is produced in the nucleus of the cell and then transported to the terminal being processed en route (Fig. 12.1). The prepropeptide is produced by translation in ribosomes and so occurs only in cell bodies or dendrites while the classical transmitters are produced at the terminal via a short series of enzymatic steps from a simple precursor. The study of the production of the propeptides have revealed a series of principles in that ... 

M. Murakami, Enhanced absorption and lymphatic transport of macromolecules via the rectal route, in Delivery Systems for Peptide Drugs (S. S. Davis, L. Ilium, and E. Tomlinson, eds.), Plenum Press, New York, 1986, p. 177. 

Penetration enhancers are low molecular weight compounds that can increase the absorption of poorly absorbed hydrophilic drugs such as peptides and proteins from the nasal, buccal, oral, rectal, and vaginal routes of administration [186], Chelators, bile salts, surfactants, and fatty acids are some examples of penetration enhancers that have been widely tested [186], The precise mechanisms by which these enhancers increase drug penetration are largely unknown. Bile salts, for instance, have been shown to increase the transport of lipophilic cholesterol [187] as well as the pore size of the epithelium [188], indicating enhancement in both transcellular and paracellular transport. Bile salts are known to break down mucus [189], form micelles [190], extract membrane proteins [191], and chelate ions [192], While breakdown of mucus, formation of micelles, and lipid extraction may have contributed predominantly to the bile salt-induced enhancement of transcellular transport, chelation of ions possibly accounts for their effect on the paracellular pathway. In addition to their lack of specificity in enhancing mem-... 

Another means of transport across the intestine is via the paracellular route, that is between the adjacent enterocytes. Water can enter the intestinal space throngh this ronte and take with it small molecnles inclnding glncose, amino acids and small peptides. This is known as solvent drag (Figure 4.7). Unfortunately, the qnantitative importance of this route is not known. 

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. 

---