Metabolism and effects on cholestasis of isoursodeoxycholic and ursodeoxycholic acids in bile duct ligated rats

Isoursodexycholic acid (isoUDCA), the 3 beta -epimer of ursodeoxycholic aci d (UDCA), may have pharmaceutical potential because of its similar hydrophi licity and in vitro cytoprotection as compared with UDCA. We compared metab olism and effects on cholestasis of UDCA and isoUDCA in experimental choles tasis in rats. Cholestasis was induced by bile duct ligation. For bile flow and biliary bile acid analysis, UDCA or isoUDCA were infused intraduodenal ly, For the study of chronic effects. chow was supplemented with 2.5 g/kg U DCA or isoUDCA for 3 weeks. Sham-operated animals served as controls. IsoUD CA 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 liv er biochemistry but not clinical and histological parameters in chronic cho lestasis. The decrease of serum cholic acid in control animals was more pro nounced 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 effec t on choleresis and liver biochemistry as UDCA. IsoUDCA features pro-drug c haracteristics of UDCA and causes compared to the latter lower serum bile a cid concentrations in non-cholestatic animals. (C) 2001 Elsevier Science B. V. All rights reserved.