Bile salt micelles solubilization

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. 

Penetration enhancers have different mechanisms of action depending on their physicochemical properties. Some examples of penetration enhancers and their mechanisms are bile salts (micellization and solubilization of epithelial lipids), fatty acids such as oleic acid (perturbation of intracellular lipids) [25,26], azone (l-dodecylazacycloheptan-2-one) (increasing fluidity of intercellular lipids), and surfactants such as sodium lauryl sulfate (expansion of intracellular spaces). The complete list of enhancers and their mechanism of actions are discussed in detail in Chapter 10. 

Figure 1-14 presents a cross-section of a bile salt micelle and the way in which the micelle solubilizes a molecule of fatty acid. The bile salt shown is taurocholate and the fatty acid is palmitic acid. Within the micelle, the fatly acid remains in solution and can diffuse over some distance. The micelle that results from addition of the fatly acid molecule is called a mixed micelle because it contains more than one type of molecule. In the absence of the bile salt, the fatty add might adhere to... 

Wiedmann TS and Kamel L. Examination of the Solubilization of Drugs by Bile Salt Micelles. yP/tfflrm 5d2002 91 1743-1764. 

The enterocytes of the small intestine can be isolated and used for study of intracellular aspects of intestinal lipid transport like triglyceride synthesis [52]. The disappearance of the mucus barrier during isolation of the epithelial cells results in plasma membrane disintegration and loss of cellular integrity when the cells are exposed to bile salts. As is the case for brush border vesicles, the system of isolated cells does not allow study of interaction between enterocytes and lipids dispersed in a form that resembles physiological conditions, i.e. solubilized in mixed bile salt micelles. 

Fat-soluble vitamins such as retinol and )3-carotene are readily dissolved in mixed lipid-bile salt micelles in vitro. Retinol is approximately 10 times more readily dissolved in such micelles than /3-carotene [105]. It is likely that these two substances occupy different regions of the micelle. The difference in solubility, therefore, may reflect the limited capacity of the nonpolar core of the micelle for the relatively bulky /3-carotene molecule. Retinol, on the other hand, may occupy a more hydrophilic region of the micelle. In a mixed oil/micellar system, a-tocopherol distributes between the two phases, its concentration in the micellar phase being enhanced by expansion of the micelles with monoglycerides and lecithin of long-chain fatty acids. However, lipids containing medium-chain fatty acids do not expand the micelles as effectively as their long-chain counterparts such that there is less solubilization of a-tocopherol in the micellar phase [106]. 

This value (A /HA) is actually the sum of the small amount of acid soluble as individual molecules plus the acid solubilized in the bile salt micelle. 

One must ask the question—why don t the rest of the bile salts form large micelles with one cholesterol molecule per micelle Unless this is a thermodynamically unstable situation the existence of two markedly different kinds of bile salt micelles in the same solution at cholesterol saturation seems unlikely since one must postulate that some bile salt micelles have a specific affinity for cholesterol while other chemically identical molecules do not. These observations may also apply to other compounds solubilized only slightly by bile salts [e.g., large fat-soluble dyes, methyl cholanthracine, griseofulvin, and glutethemide (12, 44b, 143, 147-148, 176)]. 

Matsuoka K, Kajimoto E, Horiuchi M, Honda C, Endo K (2010) Competitive solubilization of cholesterol and six species of sterol/stanol in bile salt micelles. Chem Phys Lipids 163(4-5) 397 02. doi 10.1016/j.chemphyslip. 2010.03.006... 

Certain compounds are known to achieve higher absorption rates from the GI tract if they are taken with food, and this observation has been linked to their solubilization by bile salts [74], Bile salts, especially those of cholic and deoxycholic acids, have been used to solubilize steroid hormones [75], antibiotics [76], and nonsteroidal antiinflammatory drugs [77]. For example, amphotericin B (an antifungal agent) has been solubilized for parenteral use in micelles composed of sodium desoxycholate [78], As illustrated in Fig. 11, the degree of solubilization of carbamazepine by sodium desoxycholate is minimal below the critical micelle concentration but increases rapidly above this value [79]. At sufficiently high concentrations, when the micelles become saturated in carb-amezepine, the apparent solubility reaches a limiting value approximately seven times the true aqueous solubility in the absence of desoxycholate. 

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