Sodium chenodeoxycholate

The common bile salts in humans are glycine and taurine conjugates of sodium deoxycho-late (NaDOC) and sodium chenodeoxycholate (CDOC), dihydroxy bile salts, and sodium cholate (NaC, the trihydroxy bile salt). The ability of bile salts to increase transmucosal transport of solutes has been frequently stated [62,81,82]. Generally, the more hydrophobic dihydroxy bile salts act as more effective absorption enhancers in comparison to trihydroxy bile salts. For example, Gullikson et al. [83] have reported that the absorption of inulin, dextran, and albumin in the perfused rat jejunum was enhanced with dihydroxy but not with trihydroxy bile salts. 

Fig. 38. The effect of dihydroxy and trihydroxy bile salts on the solubility of lithocholate. The upper and lower sets of three curves (Na salts, 120 mM Na salts, 25 mA/) represent the solubility of NaL as a function of temperature in varying amounts of sodium chenodeoxycholate (J), sodium deoxy-cholate (O). and sodium cholate ( ). Total bile salt concentrations are 120 mM in upper three curves and 25 mAf in lower three curves. The middle set of three curves (K salts, 120 mM) represent solubility of KL in potassium chenodeoxycholate (J), potassium deoxycholate (O), and potassium cholate ( ), at a total bile salt concentration of 120 mM (45).

A comparative study of the effect of sodium cholate, sodium deoxycholate, sodium chenodeoxycholate and taurodeoxycholate on the absorption of quin-albarbitone sodium by goldfish [105] has shown no correlation between their effectiveness as absorption promoters and their relative hydrophobicity or ability to lower interfacial tension. In general terms their ability to increase absorption is predictable because of their surface activity and their ability to abstract lipid from erythrocyte ghosts indicating their freedom to interact with biological membranes [106, 107]. 

Kandell and Bernstein published one of the earliest reports to suggest that bile acids also demonstrate DNA-damaging effects in eukaryotic cells. They showed that human foreskin fibroblasts underwent unscheduled DNA synthesis (indicating DNA repair), as measured by tritiated thymidine incorporation when cells were treated with increasing concentrations of sodium deoxycholate or chenodeoxycholate. Utilising mutant Chinese hamster ovary cells deficient in strand rejoining (EM9), the authors were able to demonstrate that the repair of deoxycholate-induced DNA damage was dependent on strand break repair capacity. 

Abbreviations OG, n-octyl- 3-D-glucopyranoside DM, dodecylmaltoside LM, w-lauryl-( -D-glucopyranoside Azone, 1-dodecyl azacyclohepatan-2-one, SCG, sodium glycocholate STDHF, sodium tauro-2425 dihydrofusidate UCDA, ursodeoxycholate CDCA, chenodeoxycholate SDS, sodium dodecylsulfate DMSO, dimethyl sulfoxide DMF, AV-dimethyl formamide DMAC, A At-dimethyl acetamide. 

Roe, J. M., and B. W. Barry. 1982. Micellar properties of sodium salts of ursodeoxycholic chenodeoxycholic, deoxycholic and cholic acidd. Pharm. PharmacoB4 (Suppl.) 24-25. 

The apical localized sodium-dependent bile add transporter (ASBT) is expressed in the human duodenum and ileum and is barely detectable in colon [16]. ASBT transports bile adds such as glycodeoxycholate and chenodeoxycholic add (XX) [49, 50]. Few examples exist where the bile acid scaffold has been used as a promoiety for a prodrug approach. ASBT has micromolar affinities for the natural substrates, and the studies on ASBT are too few to make a general statement on the potential and role of this transporter in drug absorption [49, 50]. 

A typical procedure for the isolation of the free bile acids included precipitation of the bile protein with alcohol and hydrolysis of the conjugated acids for long periods of time in from 5 to 10 percent aqueous sodium hydroxide. Different methods were then applied for the isolation of each individual acid from the resulting crude mixture of free bile acids. Cholic and deoxycholic acid could be separated from each other by the addition of concentrated barium chloride to an ammoniacal solution of the hydrolyzed acids, since most of the barium deoxycholate is precipitated with the fatty acids, whereas barium cholate remains in solution (34). The greater solubility of chenodeoxycholic acid in ether was used by Wieland for its isolation lithocholic acid, the weakest of the acids, was obtained by fractional precipitation... 

Ursodeoxycholic acid was detected very early by Hammarsten in polar bear bile (85). It was isolated in crystalline form by Shoda (58) and characterized later by Iwasaki (84). The acid, which is the 7/3-epimer of chenodeoxycholic acid, may be prepared in good yield from 7-ketolithocholic acid by reduction with sodium in propanol according to Kanazawa et al. (86). Ursodeoxycholic acid was originally considered to be a unique constituent of bear bile but has since been detected as a minor constituent in the bile of several mammals including man (2). It is also present in human feces (52). 

The electrophoretic mobilities of C-labeled cholic, deoxycholic, and chenodeoxycholic acid and their corresponding taurine and glycine conjugates were determined by Norman (42). The paper electrophoresis was performed in barbiturate buffer of ionic strength 0.1, pH 8.6, in an electric field of 7.5 V/cm for 3 hr. When 1 pg of each acid, as the sodium salt dissolved in 25 pi of water, was applied to the paper strips, the isotope determination after electrophoresis showed broad peaks all with a mean mobility similar to that of albumin or slightly lower. The electrophoretic mobilities of all of the bile acids were influenced by the concentration in the solution applied and presented difficulties in identifying bile acids in natural extracts. The migration of bile salt-lecithin micelles on paper electrophoresis has been reported by Shimura (43). The micelles were prepared by addition of lecithin to mixed bile salts, which may have also contained cholesterol. 

Figure 5 (a and b) Chemical structure of the sodium salt of several bile acids 1 cholic acid, 2 chenodeoxycholate, 3 deoxychoUc acid, 4 glycocholic acid, 5 taurochoUc acid, and 6 tauro deoxychoUc acid, (c) Structures of micelles from choUc acid derivatives, proposed by Small and coworkers. Two or four molecules assemble because of hydrophobic interactions between the cholesterol groups. The hydroxyl groups (black dots on cholesterol) and the carboxylic acids side group shield the hydrophobic domain from water. (Refs. 22-24 for cmcs and Ref. 16 for aggregation numbers.) (Reproduced with permission from Ref. 21. Indian Academy of Sciences, 2004.)... 

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