Permeability bile salts, effect

Figure 7.51 Effect of bile salt on permeability in donor well at pH 6.5.

An alternative method to overcome the solubility problem mentioned in the last section is to use bile salts to solubilize lipophilic molecules in the donor wells. Figure 7.51 shows a plot of relative permeability (Pe without bildPe with bile) versus membrane retention, which is related to lipophilicity (Section 7.7.2). As the plot shows, the most lipophilic molecules (carvedilol, propranolol, and verapamil) have attenuated permeabilities (by a factor of 3 in the case of carvedilol). The effective partition coefficient between the PAMPA membrane phase and the aqueous phase containing bile salt micelles [577] is expected to be lower for lipophilic molecules, which should result in lower Pe values. This is evident in the figure. 

Morimoto et al. [33] demonstrated that the ocular absorption of hydrophilic compounds over a wide range of molecular weights could be increased by 2 and 10 mM sodium taurocholate and sodium taurodeoxycholate in a dose-dependent manner. The compounds were glutathione (307 Da), 6-carboxyfluorescein (376 Da), FTTC-dextran (4 kDa), and insulin (5.7 kDa). Of the two bile salts, sodium taurodeoxycholate was more effective. At 10 mM, this bile salt increased the permeability of 6-carboxyfluorescein from 0.02% to 11%, glutathione from 0.08% to 6%, FITC-dextran from 0% to 0.07%, and insulin from 0.06% to 3.8%. Sodium taurocholate, on the other hand, increased the permeability to 0.13%, 0.38%, 0.0011%, and 0.14%, respectively. Taurodeoxycholate was more effective than taurocholate in the nasal epithelium as well [202], This difference in activities can possibly be attributed to their micelle-forming capability, which is higher for taurodeoxycholate, a dihydroxy bile salt [190],... 

Hersey SJ, Jackson RT (1987) Effect of bile salts on nasal permeability in vitro. J Pharm Sci. 76 876-879. 

Tokunaga, Y., S. Muranishi, and H. Sezaki. 1978. Enhanced intestinal permeability to macromolecules. I. Effect of monoolein-bile salts mixed micelles on the small intestinal absorption of heparin. J Pharmacobiodyn 1 28. 

Lastly, mention should be made of a recent study of the possible co-carcinogenic effects of bile salts in which enhanced uptake by the colon of 7,12-dimethylbenzanthracene was demonstrated in the presence of deoxycholic add [114]. It is very likely that this reflects an increase in mucosal permeability caused by this secondary bile acid. 

Noninvasive delivery of insulin via most mucosal membranes requires the use of chemical enhancement for notable insulin absorption (see Section 3.3 and Table II). However, most permeation enhancers have, in addition to their effect on the mucosal membrane, an often pronounced influence on insulin three-dimensional structures. Thus, sodium salicylate (Touitou et al, 1987) as well as bile salts (Gordon etal, 1985) have been shown to dissociate insulin oligomers into monomers. This effect improves membrane permeability, but it may also reduce the physical stability and increase the susceptibility of insulin to enzymatic degradation. The exposure of new epitopes may also influence the immunological properties of the insulin formulation. 

The bile salt promotion of insulin absorption is probably a combined effect of several factors, including dissociation of insulin oligomers (Li etal, 1992 Shao etal., 1992), inhibition ofproteolysis (Hirai etal, 1981b), and a direct effect on the permeability ofthe mucosa. However, monomers ofinsulin are not absorbed in the absence of a promoter (Pontiroli and Pozza, 1990). 

Bile salts may also influence drug absorption either by affecting membrane permeability or by altering normal gastric emptying rates, the latter having been explored by Feldman et al [246,247]. Sodium taurocholate increases the absorption of sulphaguanidine from the stomach, jejunum and ileum, the effect... 

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