Mucosal membrane permeability

Murakami, T., et al. 2000. Enhancing effect of 5 a-cyprinol sulfate on mucosal membrane permeability to sodium ampicillin in rats. Eur J Pharm Biopharm 49 111. 

Intemasal delivery of peptide and protein drugs is severely restricted by pre-systemic elimination due to enz5miatic degradation or mucociliary clearance and by the limited extent of mucosal membrane permeability. a-CyD has been shown to remove some fatty acids from nasal mucosa and to enhance the nasal absorption of leuprolide acetate in rats and dogs. The utility of chemically modified CyDs as absorption enhancers for peptide drugs in rats has been demonstrated. For example, DM-P-CyD was shown to be a potent enhancer of insulin absorption in rats, and a minimal effective concentration of DM-(3-CyD for absorption enhancement exerted only a mild effect on the in vitro ciliary movement.The scope of interaction of insulin with CyDs is limited, because CyDs can only partially include the hydrophobic amino acid residues in peptides with small stability constants. Under in vivo conditions, these complexes will readily dissociate into separate components, and hence the displacement by membrane lipids may further destabilize the complexes. The direct interaction of peptides with CyDs is therefore of minor importance in the enhancement of nasal absorption. Of the hydrophilic CyDs tested, DM- 3-CyD had the most prominent inhibitory effect on the enzymatic degradation of both BLA and insulin in rat nasal tissue homogenates. Because of the limited interaction between peptides and CyDs,... 

Precellular solute ionization dictates membrane permeability dependence on mucosal pH. Therefore, lumenal or cellular events that affect mucosal microclimate pH may alter the membrane transport of ionizable solutes. The mucosal microclimate pH is defined by a region in the neighborhood of the mucosal membrane in which pH is lower than in the lumenal fluid. This is the result of proton secretion by the enterocytes, for which outward diffusion is slowed by intestinal mucus. (In fact, mucosal secretion of any ion coupled with mucus-restricted diffusion will provide an ionic microclimate.) Important differences in solute transport between experimental systems may be due to differences in intestinal ions and mucus secretion. It might be anticipated that microclimate pH effects would be less pronounced in epithelial cell culture (devoid of goblet cells) transport studies than in whole intestinal tissue. 

Membrane uptake of nonionized solute is favored over that of ionized solute by the membrane/water partition coefficient (Kp). If Kp = 1 for a nonionized solute, membrane permeability should mirror the solute ionization curve (i.e., membrane permeability should be half the maximum value when mucosal pH equals solute pKa). When the Kp is high, membrane uptake of nonionized solute shifts the ionization equilibrium in the mucosal microclimate to replace nonionized solute removed by the membrane. As a result, solute membrane permeability (absorption rate) versus pH curves are shifted toward the right for weak acids and toward the left for weak bases (Fig. 7). 

Figure 7 (Left panel) Relative absorption rate for a weak acid (pKa = 3) as a function of mucosal pH for increasing barrier (membrane) permeability (Pb) with fixed unstirred aqueous layer permeability (Pul). X = pHinflectionpoint in Eq. (4). (Right panel) Partition coefficient-dependent absorption rates for salicylic acid and the weak base ephedrine. (From Ref. 19.)...

Recent work in our laboratory (Kompella, Mathias, and Lee, unpublished observation) has revealed that activation of the cAMP-regulated Cl channels in the conjunctiva also enhances the transcytosis of horseradish peroxidase. 8-Bromo-cAMP (a membrane-permeable analog of cAMP) and terbutaline (a p2-adrenergic agonist known to increase intracellular levels of cAMP in other epithelial tissues [238]), at 0.5 mM, were found to enhance the transport of 100 pg/ mL HRP from the mucosal side to the serosal side of the pigmented rabbit conjunctiva by a factor of 4 (Fig. 11). 

Wu S-Y, Robinson JR (1999) Transcellular lipophilic complex-enhanced intestinal absorption of human growth hormone. Pharm Res 16 1266-1272 Yamashita S, Saitoh H, Nakanishi K, Masada M, Nadai T, Kimura T (1987) Effects of diclofenac sodium and disodium ethylenediaminetetraacetate on electrical parameters of the mucosal membrane and their relation to the permeability enhancing effects in the rat jejunum. J Pharm Pharmacol 39 621-626... 

Penetration enhancers have been investigated for most mucosal and epithelial routes (see Sections 6.7.4, 8.5.3 and 9.7.1 for further details). The major challenge that remains is to find enhancers that will reversibly increase membrane permeability without causing toxicity during long-term use. Various surfactants and protease inhibitors have been reported to increase the pulmonary absorption of peptides and proteins on an experimental basis but their clinical use is not established and the current general consensus seems to be against their inclusion in pulmonary formulations. 

Due to a combination of poor membrane permeability and metabolism at the site of absorption, rectal bioavailability of peptide and proteins is low. As in other mucosal bioavailability testing, insulin is the most studied polypeptide with respect to rectal absorption. 

Although the objective of most absorption enhancers is to avoid direct interaction with the mucosal membrane, cell permeation enhancers use this as a means to increase drug absorption. One form of enhancer currently of interest consists of glycosylated molecules, or facial amphiphiles. It is claimed that these compounds temporarily increase membrane permeability. Molecules are designed to self-assemble in membranes to form transient pores that permit hydrophilic com-poimds to cross the membrane. This technology has considerable potential for absorption enhancement. No adverse effects have been reported to date. ... 

It is less clear, however, what proportion of sterol reaching the lymph is derived from other luminal sources, particularly when the diet contains little or no cholesterol. This problem has been approached in several ways. One is to feed a newly available, non-absorbable polymer called surfbmer that binds to the mucosal membrane of the intestine and reduces the passive permeability coefficient for hydrophobic molecules such as cholesterol. In animals fed this polymer and only trace quantities of... 

FIGURE 1-2 Influence of pH on the partitioning of a weak acid (pK = 4.4) between plasma (pH = 7.4) and gastric juice (pH = 1.4) separated by a lipid barrier. The gastric mucosal membrane behaves as a lipid barrier permeable only to die lipid-soluble, nonionized form of the acid. The ratio of nonionized to ionized drug at each pH is readily calculated from die Henderson-Hasselbalch equation diat relates die pH of the medium and die drug s dissociation constant (p ) to the ratio of the protonated (HA) and unprotonated (A") forms. The same principles apply to drugs that are weak, bases (BH B -l- H ). 

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