Metabolism, pharmacokinetics, and activity of a new 6-fluoro analogue of ursodeoxycholic acid in rats and hamsters.
OBJECTIVE
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.
Roda
A
A
Dipartimento di Scienze Farmaceutiche, Università di Bologna, Italy.
Pellicciari
R
R
Polimeni
C
C
Cerrè
C
C
Forti
G C
GC
Sadeghpour
B
B
Sapigni
E
E
Gioacchini
A M
AM
Natalini
B
B
D000418:Albumins / Q000378:metabolism; D000818:Animals; D001646:Bile / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury; D006224:Cricetinae; D006863:Hydrogen-Ion Concentration; D008107:Liver Diseases / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D008647:Mesocricetus; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013655:Taurochenodeoxycholic Acid / Q000009:adverse effects*; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology
C092780:6-fluoro-ursodeoxycholic acid; D000418:Albumins; D013655:Taurochenodeoxycholic Acid; D014580:Ursodeoxycholic Acid