Naturally Occurring Bile Salts

Rastogi et al." ° published a study on enhancing the pharmacological efficacy of protein-loaded PCL-PEG-based polymerosomes. Insulin was selected as the model protein and was complexed with sodium deoxycholate, a naturally occurring bile salt. The prepared surfoplexes were efficiently encapsulated in PCL- and PEG-based polymer vesicles. It was found that with this drug delivery system, the initial burst effect was greatly reduced, and the therapeutic effect of insulin was increased by 2 h. 

Ionic detergents such as sodium dodecyl sulfate (SDS) and naturally occurring bile salts such as deoxycholate. 

The most successful therapy for cholestasis of pregnancy has been ursodeoxycholic acid (Figure 33-1). Ursodeoxycholic acid is a naturally occurring bile acid, which, when administered, relieves both pruritus and liver function abnormalities. Experimental evidence suggests that it protects hepa-tocytes and cholangiocytes from bile acid-induced cytotoxicity and improves hepatobiliary excretion. Additionally, it decreases bile salt transfer to the fetus and improves the secretory function of placental trophoblast cells. Ursodeoxycholic acid is recycled through the enterohepatic circulation. 

The natural distribution and the chemical structure of bile alcohols and primitive bile acids indicate that these compounds found in lower vertebrates are evolutionary precursors of the common bile acids found in mammalian species. Haslewood proposed that the mechanism of conversion of cholesterol to the common bile acids in mammals is a recapitulation of the evolution of bile salts and thus would entail the intermediary formation of bile alcohols and primitive bile adds similar to or the same as those found in lower species [120]. Thus, studies have been carried out to test whether the naturally occurring bile alcohols and primitive bile acids are intermediates in the biosynthetic pathway between cholesterol and the C24 bile acids in mammals. There is no doubt that such studies contributed to the elucidation of the sequence of reactions in the biosynthesis of the mammalian C24 bile acids. 

Some examples of sterols and steroids are given in Figure 9.1. Also included in this Figure are some examples of bile salts. You should realise that the structures shown are only a few of the many hundreds of compounds which occur in nature. All of these compounds include the steroidal ring structure which is numbered as shown below. 

Again, the answer should be fairly obvious. The potential therapeutic value of the steroid hormones makes these of tremendous commercial value. The commercial market for these is of the order of hundreds of millions of dollars per year. There is no comparable market for sterols and bile salts. We are faced with the interesting situation, therefore, that sterols are relatively abundant in natural sources but of relatively low commercial value, whilst steroids occur naturally at very low concentrations but are of great commercial value. Although there are tremendous variations amongst different products, steroids with desirable properties command market prices that are (ten to one thousand fold) greater than their sterol counterparts. 

The use of mixed micelles for chiral recognition was discussed in Section 5.3.3, using cyclodextrins. In addition to cyclodextrins, however, metal-amino acid complexes can also be used in a mixed mode arrangement. Bile salts are naturally occurring chiral surfactants that can be used as alternatives to, or in addition to, SDS for chiral recognition. In the presence of SDS, the migration times are faster. Table 5.5 shows initial operating conditions that can be used in chiral CE as a start to methods development.40... 

Naturally occurring micellar systems, such as phospholipids and bile salts (e.g. cholic and desoxycholic acids, as well as surfactants affect the rates of numerous chemical reactions in vivo and in vitro (Hanahan, 1960 Kavanau, 1965 Knaak et al., 1966a, b Elworthy et al., 1968 Marriott, 1969). The effects of micellization on enzymatic reactions and other biochemical processes have been discussed by Elworthy et al. (1968), Jencks (1969), and Mysels (1969). 

Conceptually. CE enantioseparations are mainly applied to charged SAs. Micellar electrokinetic chromatography (MEKC) (introduced by Terabe et al. in 1984 488 ), in contrast, permits the separation of electrically neutral compounds. In enantiomer separation by MEKC. ionic pseudo-stationary phases, such as chiral micelles composed of chiral SO moieties, which migrate according to their electrophoretic mobility, may interact stereoselectively with the solutes to be separated. MEKC with synthetic (e.g. A-dodecoxycarbonylvalines, commercialized as SDVal by Waters) 1489.490) or naturally occurring chiral surfactants (e.g. bile salts) 1491-494). and cyclodextrin-moditied MEKC (most often SDS/CD combinations) 1495-498) are the mo.st widely used selector systems in MEKC. The topic of MEKC enantioseparation has been reviewed by Nishi )499). 

Naturally occurring vitamin K is absorbed from the intestines only in the presence of bile salts and other lipids through interaction with chylomicrons. Therefore, fat malabsorptive diseases can result in vitamin K deficiency. 

Qf the naturally occurring surfactants, the bile salts and phospholipids are of particular importance. 

Steroids are a naturally occurring family of organic molecules of biochemical and medical interest. A great deal of controversy has surrounded various steroids. We worry about the amount of cholesterol in the diet and the possible health effects. We are concerned about the use of anabolic steroids by athletes wishing to build muscle mass and improve their performance. However, members of this family of molecules derived from cholesterol have many important functions in the body. The bile salts that aid in the emulsification and digestion of lipids are steroid molecules, as are the sex hormones testosterone and estrone. 

The solubility of clofazimine was enhanced in aqueous micellar systems, containing both naturally occuring surfactants e.g bile salts, and synthetic surfactants, e.g the non ionic Cremophor EL and Triton XI00, and the anionic sodium dodecyl sulphate. The incorporation of fatty acids to form mixed micelles brought about a further enhancement in drug solubility in the case of naturally occuring surfactants (approximately 300 fold with sodium cholate linoleic acid relative to buffer). In contrast, with synthetic surfactants this enhancement decreased (Fahelelbom et al., 1991 O Driscoll et al., 1991). 

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