METABOLISM, PHARMACOKINETICS, AND ACTIVITY OF A NEW 6-FLUORO ANALOG 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 lipo philicity of the 6-fluoro analogue in aqueous solution were determined and compared with those of natural analogues. Stability toward 7-dehy droxylation was assessed in human stools, pharmacokinetics and metabol ism were evaluated in bile fistula rats and hamsters, accumulation in bile with long-term feeding was assessed in the hamsters, and the abil ity to prevent the hepatotoxic effects of taurochenodeoxycholic acid w as evaluated in bile fistula rats after intraduodenal coinfusion. Resu lts: 6-Fluoro-ursodeoxycholic acid was more stable than its parent mol ecule toward 7-dehydroxylation, it was efficiently secreted in bile, a nd its total recovery was very high. With long-term administration of 6-fluoroursodeoxycholic acid, taurine and glycine amidates accounted f or more than 60% of the total biliary bile acids (15% ursodeoxycholic acid). The 6-fluoro analogue prevented the hepatotoxic effects of taur ochenodeoxycholic acid. Conclusions: The results suggest that 6-fluoro -ursodeoxycholic acid has considerable potential as a pharmaceutical a gent in the treatment of cholestatic liver disease.