Metabolism, pharmacokinetics, and activity of a new 6-fluoro analogue of ursodeoxycholic acid in rats and hamsters.
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.[1]References
- Metabolism, pharmacokinetics, and activity of a new 6-fluoro analogue of ursodeoxycholic acid in rats and hamsters. Roda, A., Pellicciari, R., Polimeni, C., Cerrè, C., Forti, G.C., Sadeghpour, B., Sapigni, E., Gioacchini, A.M., Natalini, B. Gastroenterology (1995) [Pubmed]
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