Metabolism and effects on cholestasis of isoursodeoxycholic and ursodeoxycholic acids in bile duct ligated rats.
Isoursodeoxycholic acid (isoUDCA), the 3 beta-epimer of ursodeoxycholic acid (UDCA), may have pharmaceutical potential because of its similar hydrophilicity and in vitro cytoprotection as compared with UDCA. We compared metabolism and effects on cholestasis of UDCA and isoUDCA in experimental cholestasis in rats. Cholestasis was induced by bile duct ligation. For bile flow and biliary bile acid analysis, UDCA or isoUDCA were infused intraduodenally. For the study of chronic effects, chow was supplemented with 2.5 g/kg UDCA or isoUDCA for 3 weeks. Sham-operated animals served as controls. IsoUDCA became completely converted to UDCA in the liver. Choleresis and biliary bile acids were the same after the intraduodenal administration of either compound. Oral administration of UDCA or isoUDCA significantly improved liver biochemistry but not clinical and histological parameters in chronic cholestasis. The decrease of serum cholic acid in control animals was more pronounced after isoUDCA (-93%) than after UDCA (-76%). Only after UDCA, this decrease was compensated by increases of UDCA, beta-muricholic acid (MCA), and Delta(22)-beta-MCA. Our results show that isoUDCA has the same effect on choleresis and liver biochemistry as UDCA. IsoUDCA features pro-drug characteristics of UDCA and causes compared to the latter lower serum bile acid concentrations in non-cholestatic animals.
Purucker
E
E
Department of Internal Medicine III, Medical Faculty, Aachen University of Technology, Germany. epurucker@post.klinikum.rwth-aachen.de
Marschall
H U
HU
Winograd
R
R
Matern
S
S
D000818:Animals; D001646:Bile / Q000378:metabolism; D001647:Bile Acids and Salts / Q000097:blood / Q000652:urine; D001652:Bile Ducts / Q000502:physiology* / Q000601:surgery; D001835:Body Weight; D002779:Cholestasis / Q000378:metabolism*; D002793:Cholic Acids / Q000032:analysis; D004435:Eating; D008026:Ligation; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008111:Liver Function Tests; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*
D001647:Bile Acids and Salts; D002793:Cholic Acids; C004821:muricholic acid; D014580:Ursodeoxycholic Acid; C106883:isoursodeoxycholic acid