STUDY OF HUMAN ISOURSODEOXYCHOLIC ACID METABOLISM

Background/Aims: The aim of this study was to examine the metabolism o f isoursodeoxycholic acid (isoUDCA) in humans. Methods: IsoUDCA was sy nthesized of >99% purity and administered orally for 1 week, 3 x 250 m g/day, to six healthy male subjects. Bile acids were extracted from du odenal bile, serum, and 24-h urine samples collected before and at the end of the study period, separated into groups of conjugates, and ana lyzed by gas chromatography-mass spectrometry and fast atom bombardmen t mass spectrometry. Results: IsoUDCA was tolerated without any side e ffect. Liver function tests did not change. Bile acid concentrations ( mean+/-SEM) increased from 11.9+/-1.87 to 15.3+/-1.37 mmol/l in bile ( n.s.), and from 3.4+/-0.10 to 6.8+/-0.43 mu mol/l in serum (p<0.05). U rinary excretion of bile acids increased from 5.3+/-0.29 to 82.2+/-7.8 4 mu mol/24 h (p<0.01). All changes were due to significant increases of isoUDCA and UDCA in bile, serum and urine, and of 3-dehydro-UDCA, t he 3-ore intermediate of isomerization, in bile and in serum. The rela tive enrichments of isoUDCA, UDCA, and 3-dehydro-UDCA, were: in bile, 2.2%, 25.7%, and 0.7%; in serum, 24.7%, 23.5%, and 6.1%; and in urine, 83.7%, 2.0%, and 2.4%. Whereas 78% of serum isoUDCA was unconjugated, 93-94% of biliary and urinary isoUDCA was conjugated with N-acetylglu cosamine. Conclusions: This study indicates good tolerance and signifi cant intestinal absorption of orally administered isoUDCA. IsoUDCA is extensively isomerized, probably both by intestinal and hepatic enzyme s to yield UDCA which became the major biliary compound. In vitro, usi ng the human hepatoblastoma cell line Hep G2, isoUDCA was found to be cytoprotective towards ethanol-induced cell injuries.