PH-SOLUBILITY RELATIONS OF CHENODEOXYCHOLIC AND URSODEOXYCHOLIC ACIDS - PHYSICAL-CHEMICAL BASIS FOR DISSIMILAR SOLUTION AND MEMBRANE PHENOMENA

  • 1 January 1980
    • journal article
    • research article
    • Vol. 21  (1) , 72-90
Abstract
The electrochemical properties, apparent pK (pK''a), precipitation pH and undissociated bile acid solubilities of chenodeoxycholic acid and its 7.beta. epimer, ursodeoxycholic acid and their glycine conjugates were studied by titration as functions of a number of physical-chemical variables. Despite comparable pK''a values, ursodeoxycholic acid and its glycine conjugate precipitated from H2O (37.degree. C) at pH values of 8.0-8.1 and 6.5-7.4, whereas chenodeoxycholic acid and its glycine conjugate precipitated at pH values of 7.0-7.1 and 4.8-5.0, respectively. These differences were related to the low solubility of undissociated ursodeoxycholic acid in water (53 .mu.M) and in ursodeoxycholic micelles (saturation ratio of anion:acid, 90-400:1) compared with the higher solubility of chenodeoxycholic acid in water and in chenodeoxycholate micelles (250 .mu.M and 5-25:1, respectively). In model bile systems, including those composed of conjugated ursodeoxycholate-chenodeoxycholate mixtures, ursodeoxycholic acid was less soluble than chenodeoxycholic acid and induced the mixtures to gel between pH 7.0 and 4.5-6.5. In vivo the solubility and absorption of oral ursodeoxycholic acid from the duodenum-jejunum may be limited. Ursodeoxycholic acid precipitates in the colon at pH values < 8.0, but chenodeoxycholic acid is soluble at pH values > 6.9 and hence is capable of eliciting a secretory diarrhea. The precipitation pH of glycoursodeoxycholic acid, the predominant bile acid in bile during [human] therapy with ursodeoxycholic acid, falls within the physiological range, thus this bile acid may short-circuit the entero-hepatic circulation and even precipitate from bile or gut luminal contents as crystals.