Metabolism, pharmacokinetics, and activity of a new 6-fluoro analogue of ursodeoxycholic acid in rats and hamsters.

Abstract

BACKGROUND/AIMS:

The effectiveness of ursodeoxycholic acid in treating biliary liver diseases is limited by low bioavailability and moderate activity. A new analogue of ursodeoxycholic acid was synthesized with a fluorine atom in position 6 because this should have resulted in an analogue more hydrophilic than ursodeoxycholic acid but with similar detergency.

METHODS:

After synthesis, detergency, solubility, and lipophilicity of the 6-fluoro analogue in aqueous solution were determined and compared with those of natural analogues. Stability toward 7-dehydroxylation was assessed in human stools, pharmacokinetics and metabolism were evaluated in bile fistula rats and hamsters, accumulation in bile with long-term feeding was assessed in the hamsters, and the ability to prevent the hepatotoxic effects of taurochenodeoxycholic acid was evaluated in bile fistula rats after intraduodenal coinfusion.

RESULTS:

6-Fluoro-ursodeoxycholic acid was more stable than its parent molecule toward 7-dehydroxylation, it was efficiently secreted in bile, and its total recovery was very high. With long-term administration of 6-fluoro-ursodeoxycholic acid, taurine and glycine amidates accounted for more than 60% of the total biliary bile acids (15% ursodeoxycholic acid). The 6-fluoro analogue prevented the hepatotoxic effects of taurochenodeoxycholic acid.

CONCLUSIONS:

The results suggest that 6-fluoro-ursodeoxycholic acid has considerable potential as a pharmaceutical agent in the treatment of cholestatic liver disease.

• Authors: A Roda, R Pellicciari, C Polimeni, C Cerrè, G C Forti, B Sadeghpour, E Sapigni, A M Gioacchini, B Natalini
• Journal: Gastroenterology (Gastroenterology) Vol. 108 Issue 4 Pg. 1204-14 (Apr 1995) ISSN: 0016-5085 [Print] United States
• PMID: 7698590 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 6-fluoro-ursodeoxycholic acid
• Albumins
• Taurochenodeoxycholic Acid
• Ursodeoxycholic Acid

Topics

• Albumins (metabolism)
• Animals
• Bile (metabolism)
• Chemical and Drug Induced Liver Injury
• Cricetinae
• Hydrogen-Ion Concentration
• Liver Diseases (metabolism, prevention & control)
• Male
• Mesocricetus
• Protein Binding
• Rats
• Rats, Sprague-Dawley
• Solubility
• Taurochenodeoxycholic Acid (adverse effects)
• Ursodeoxycholic Acid (analogs & derivatives, metabolism, pharmacokinetics, pharmacology)