METABOLISM, PHARMACOKINETICS, AND ACTIVITY OF A NEW 6-FLUORO ANALOG OF URSODEOXYCHOLIC ACID IN RATS AND HAMSTERS

被引:20
作者
RODA, A
PELLICCIARI, R
POLIMENI, C
CERRE, C
FORTI, GC
SADEGHPOUR, B
SAPIGNI, E
GIOACCHINI, AM
NATALINI, B
机构
[1] UNIV BOLOGNA, DIPARTIMENTO FARMACOL, I-40126 BOLOGNA, ITALY
[2] UNIV PERUGIA, IST CHIM FARMACEUT, I-06100 PERUGIA, ITALY
关键词
D O I
10.1016/0016-5085(95)90221-X
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
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-fluoroursodeoxycholic 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.
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页码:1204 / 1214
页数:11
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