Bile salts permeability

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],... 

KM Morimoto, T Nakai, K Morisaka. (1987). Evaluation of permeability enhancement of hydrophilic compounds and macromolecular compounds by bile salts through rabbit corneas in vitro. J Pharm Pharmacol 39 124-126. 

Nielsen HM, Rassing MR (1999a) TR146 cells grown on filters as a model of human buccal epithelium III. Permeability enhancement by different pH values, different osmolality values, and bile salts. Int J Pharm 185 215-225... 

Senel S, Hoogstraate AJ, Spies F, Verhoef JC, Bos-van Geest A, Junginger HE, Bodde HE (1994) Enhancement of in vitro permeability of porcine buccal mucosa by bile salts Kinetic and histological studies. J Control Release 32 45-56... 

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

Several ehemical enhancers, such as sodium ethylenediaminetetraacetate and sodium taurocholate, oleic acid [37], polyoxyethylated nonionic surfactants, citric acid, and dihydroxy bile salts open the paracellular route, presumably by disruption of the intraeellular OJC funetion [37], The use of nitrie oxide is another approach [39], Moreover, manipulation of the cyclooxygenase pathway activities to trigger the release of eompounds like substance P may provide another means for altering colonic permeability [40],... 

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. 

Fatty acids [25], monoglycerides [25], fatty acid-bile salt micelles [26], and surfactants [27] have all been shown to increase epithelial membrane permeability by affecting the membrane proteins or lipids [28]. 

Penetration enhancers act by increasing the permeability of the corneal cell membrane and/or loosening the tight junctions between the epithelial cells, which primarily restrict the entry of molecules via the paracellular pathway. Classes of penetration enhancers include surfactants, bile salts, calcium chelators, preservatives, fatty acids, and some glycosides such a saponin. 

Bile salts are amphiphilic molecules that are surface active and self-associate to form micelles in aqueous solution. They increase corneal permeability by changing the rheological properties of the bilayer [231], A number of bile salts such as deoxy-cholate, taurodeoxycholate, and glycocholate have been tested so far, and it was suggested, that a difference in their physicochemical properties (solubilizing activity, lipophilicity, Ca2+ sequestration capacity) is probably related to their performance as permeability-enhancing agents [36]. 

Bile salts, which are surface active, promote dissolution of lipophilic drugs and lipophilic drug formulations, enteric coatings, and waxy drug matrices. Bile salts may also promote membrane permeability of lipophilic molecules through micelle formation and solubilization. 

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