Glycocholate

Mammalian bile contains sodium salts of conjugated bile acids, e.g. glycocholic acid and taurocholic acid, in which cholic acid is combined (amide linkage) with glycine and taurine respectively. 

Sodium glycocholate [863-57-0] M 488.6. Dissolved in EtOH, filtered and concentrated to crystallisation, and recrystallised from a little EtOH. 

The most prevalent steroid in animal cells is cholesterol (Figure 25.30). Plants contain no cholesterol, but they do contain other steroids very similar to cholesterol in structure (see page 256). Cholesterol serves as a crucial component of cell membranes and as a precursor to bile acids (e.g., cholate, glycocholate,... 

Bile acids, which exist mainly as bile salts, are polar carboxylic acid derivatives of cholesterol that are important in the digestion of food, especially the solubilization of ingested fats. The Na and salts of glycocholic acid and tauro-cholic acid are the principal bile salts (Ligure 25.41). Glycocholate and tauro-cholate are conjugates of cholic acid with glycine and taurine, respectively. 

FIGURE 25.41 Cholic acid, a bile salt, is synthesized from cholesterol via 7o -hydroxy-cholesterol. Conjugation with taurine or glycine produces taurocholic acid and glycocholic acid, respectively. Taurocholate and glycocholate are freely water-soluble and are highly effective detergents. 

Glyko-cholsaure, /. glycocholic acid, -gallus-silure. /. glucogallic acid. 

Bile acids The organic acids in bile contains sodium glycocholate and sodium taurocholate, cholesterol, biliverdin and bilirubin, mucus, fat, lecithin, and cells and cellular debris. 

These general observations have been confirmed in PAMPA measurements in our laboratory, using the 2% DOPC-dodecane lipid. With very lipophilic molecules, glycocholic acid added to the donor solution slightly reduced permeabilities, taurocholic acid increased permeabilities, but SLS arrested membrane transport altogether in several cases (especially cationic, surface-active drugs such as CPZ). 

Although the ocular absorption of peptide as well as nonpeptide drugs is poor [96,196-198], the ocular route is by far the least studied for the usefulness of penetration enhancers. This is in part due to the perceived sensitivity of ocular tissues to irritation and the fear of corneal and conjunctival damage caused by the enhancers. Whereas the rat nasal epithelium may tolerate up to 5% sodium glycocholate [199], ocular administration of sodium glycocholate at a concentration of 2% and beyond induces reddening of the eye and tear production in rabbits (Kompella and Lee, unpublished observation). 

Conjunctival insulin absorption in rabbits estimated as plasma insulin levels after punctal occlusion was also shown to be increased by bile salts (sodium deoxycholate, glycocholate, and taurocholate) and a surfactant (polyoxyethylene-9-lauryl ether) [200], Their rank order of effectiveness at 1% was sodium deoxycholate > polyoxyethylene-9-lauryl ether > sodium glycocholate = sodium taurocholate. There was an 18-, 29-, 3-, and 3-fold increase, respectively, in conjunctival absorption. Sodium deoxycholate, a dihydroxy bile salt, was more effec-... 

The literature survey in this section suggests that the ideal in vitro permeability assay would have pH 6.0 and 7.4 in the donor wells, with pH 7.4 in the acceptor wells. (Such a two-pH combination could differentiate acids from bases and non-ionizables by the differences between the two Pe values.) Furthermore, the acceptor side would have 3% wt/vol BSA to maintain a sink condition (or some sinkforming equivalent). The donor side may benefit from having a bile acid (i.e., taurocholic or glycocholic, 5-15 mM), to solubilize the most lipophilic sample molecules. The ideal lipid barrier would have a composition similar to those in Table 3.1, with the membrane possessing a substantial negative charge (mainly from PI). Excessive DMSO/other co-solvents would be best avoided, due to their unpredictable effects. 

Recently, molecular biology studies have been carried out on hepatic uptake transporters. With regard to the Na+-dependent hepatic uptake of bile acids, Na+-taurocholate cotransporting polypeptide (Ntcp/NTCP) has been cloned from both rodents and humans [14-17]. Ntcp/NTCP accepts bile salts, such as taurocholate and glycocholate, as well as some anionic compounds such as dehydroepian-drosterone sulfate and bromosulfophthalein [16, 18]. However, the presence of unidentified Na+-dependent transporters for anionic drugs (e.g., bumetanide) has also been suggested [19, 20]. 

Bile salt export pump (BSEP gene symbol ABCB11) mediates the biliary excretion of nonconjugated bile salts, such as taurocholic acid, glycocholic acid and cholic acid, and therefore is responsible for the formation of the bile acid-dependent bile flow [97, 98]. Its hereditary defect results in the acquisition of PFIC2, a potentially lethal disease which requires liver transplantation [17, 81, 82, 99]. As discussed in Section 12.5.2, the inhibition of BSEP following drug administration may result in cholestasis. 

Lewis, as already mentioned, used a solution of sodium glycocholate and determined the adsorption of the salt by a surface of paraffin oil. The interfacial tension solution—paraffin oil this was measured for a number of concentrations by the drop method just discussed, and the [Pg.42]

Those of complex constitution and high molecular weight, e.g., sodium glycocholate, Congo red, methyl orange, sodium oleate, which show adsorption 20—100 times larger than that calculated from the formula. 

Glycocholic Acid.—Fresh ox bile (2-0-2 5 1.) is obtained from a... 

Occasionally the glycocholic acid does not crystallise from the acidified bile until several days have elapsed. Frequent shaking has an accelerating effect. With summer bile the experiment often fails because the components of such bile crystallise with more difficulty. As far as experience goes, this has never been the case in winter. 

Nielsen HM, Verhoef JC, Ponec M, Rassing MR (1999b) TR146 cells grown on filters as a model of human buccal epithelium Permeability of fluorescein isothiocyanate-labelled dextrans in the presence of sodium glycocholate. J Control Release 60 223-233... 

Senel S, Duchene D, Hincal AA, Capan Y, Ponchel G (1998) In vitro studies on enhancing effect of sodium glycocholate on transbuccal permeation of morphine hydrochloride. J Control Release 51 107-113... 

Faraj et al. [28] studied the effects of different concentrations of leucine enkephalin, peptidase inhibitors, and sodium glycocholate (GC) on the stability and absorption of leucine enkephalin in nasal cavities of rats. Based on the study, the rate and extent of formation of des-tyrosine leucine enkephalin... 

Mixed micelles (e.g., monoolein taurocholate, oleic acid taurocholate, oleic acid-polyoxyethylene hydrogenated castor oil (HCO 60), and oleic acid glycocholate)... 

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