Absorption membrane penetration

Octanol-water partition (log P) and distribution (log D) coefficients are widely used to make estimates for membrane penetration and permeability, including gastrointestinal absorption [77, 78], BBB crossing [60, 69] and correlations to pharmacokinetic properties [1]. The two major components of lipophilicity are molecular size and H-bonding [57], which each have been discussed above (see Sections 2.5 and 2.6). 

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. 

Glycosylation has also been reported to improve intestinal absorption of peptide drugs which demonstrate poor membrane penetrability. For instance, glycosylation at the /V-terminus of tetrapeptide (Gly-Gly-Tyr-Arg) increases its resistance to degradation by peptidases in addition, Na+-dependent glucose transporters were shown to play an important role in the intestinal absorption of both /)-(succinylamido)phenyl a- or p-D-ghicopyranosides (Nomoto et al. 1998). 

Although it is the ionized form of a drag that is required for aqueous solubility, the unionized form is required for lipid solubility and transcellular passive diffusion. However, the unionized form has poor aqueous solubility, which mitigates against membrane penetration. In practice, a balance between the lipid and aqueous solubility of a drag is required for successful absorption. 

Increasing the lipid character of a hydrophilic drag molecule may enhance its membrane-penetrative properties and thus improve oral bioavailability. In particular, lipidization strategies have been investigated for the oral absorption of therapeutic peptides and proteins, which are generally hydrophilic compounds. 

The second property of importance for bioavailability is the polar surface area (PSA) that is associated with intestinal absorption and cell membrane penetration by passive transport. Compounds with a high polar surface are less likely to penetrate the lipophilic environment of the cell membranes by passive transport. Like the logP, PSA can be computed by summing up fragment contributions (8) with H-bonding fragments as the main contributor. 

During the intervening time many of these areas have changed, some more than others. There also have been changes in emphasis, reflected particularly in the rapidly expanding interest and discoveries in membrane penetration, exploitation of various dosage routes, formulation factors, and absorption enhancers. 

The hydrated nature of amino acid residues lining the porin channels presents an energetically unfavourable barrier to the passage of hydrophobic molecules. In rough strains, the reduction in the amount of polysaccharide on the cell surface allows hydrophobic molecules to approach more closely the surface of the outer membrane and cross the outer membrane lipid bilayer by passive diffusion. This process is greatly facilitated in deep rough and heptose-less strains which have phospholipid molecules on the outer face of their outer membranes as well as on the inner face. The exposed areas of phospholipids favour the absorption and penetration of the hydrophobic agents. 

One of the first set of surfaces that the substance will encounter immediately after absorption will be those present within the blood, namely the latter s cell constituents and plasma proteins (PP). Blood cells will have membrane penetration barriers akin to those... 

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