Membrane transport proteins absorption enhancement

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. 

Miscellaneous Toxicity Concerns. Additional toxicity concerns include interference with normal metabolism and function of mucosal cells, e.g., water absorption by these cells. The unconjugated bile acids are known to block amino acid metabolism and glucose transport. There is a possibility of biotransformation of these enhancers to toxic or carcinogenic substances by hepatic monooxygenases. Absorption of permeation enhancers into the systemic circulation can also cause toxicity, e.g., azone and hexamethylene laur-amide, which are absorbed across skin. Moreover, changes in membrane fluidity may alter the activity of membrane-bound transport proteins and enzymes. 

An intestinal epithelial cell, like all epithelial cells, is said to be polarized because the apical and basolateral domains of the plasma membrane contain different sets of proteins. These two plasma-membrane domains are separated by the tight junctions between cells. The apical portion of the plasma membrane, which faces the Intestinal lumen, is specialized for absorption of sugars, amino acids, and other molecules that are produced from food by various digestive enzymes. Numerous fingerlike projections (100 nm in diameter) called microvilli greatly increase the area of the apical surface and thus the number of transport proteins it can contain, enhancing the cell s absorptive capacity. 

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-... 

Permeation enhancers improve the absorption of protein and peptides by increasing their paracellular and transcellular transports. An increase in paracellular transport is mediated by modulating the tight junctions of the cells, and an increase in transcellular transport is associated with an increase in the fluidity of the cell membrane. Chapter 2 describes in depth the various paracellular and transcellular transport pathways, which will not be discussed here. 

Protein degradation continues in the lumen of the intestine. The pan creas secretes a variety of proteolytic enzymes into the intestinal lumen as inactive zymogens that are then converted into active enzymes (Sections 9.1 and 10.4). The battery of enzymes displays a wide array of specificity, and so the substrates are degraded into free amino acids as well as di- and tripeptides. Digestion is further enhanced by proteolytic enzymes, such as aminopeptidase N, that are located in the plasma membrane of the intestinal cells. Aminopeptidases digest proteins from the amino-terminal end. Single amino acids, as well as di- and tripeptides, are transported into the intestinal cells from the lumen and subsequently released into the blood for absorption by other tissues (Figure 23.1). 

Epithelia sometimes have a secretory function (in the liver), but otherwise function as a barrier between the external environment and the internal environment. They also selectively transport substances between compartments. To enhance this task, the outward-facing membrane, called the apical membrane, is often covered by microvilli (small, finger-like protrusions that increase surface area for absorption). The inward-facing membrane, called the basolateral membrane, has a different lipid and protein composition from the apical membrane. Because of these specialized structures, and the tight junctions between cells, the only substances that normally enter the body from the outside are those transported through the cells. 

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