Isoursodeoxycholic acid : metabolism and therapeutic effects in primary biliary cirrhosis 1

Significant amounts of ursodeoxycholic acid (UDCA) used for the treatment of patients with primary biliary cirrhosis (PBC) become epimerized at C-3 to isoUDCA. We investigated the metabolism of isoUDCA and a possible pharmacologic effect in five patients (51.4 5.8 years old; 3 females, 2 males) with PBC and persistent elevations of -glutamyl transpeptidase ( -GT) and alkaline phosphatase despite treatment with UDCA for more than one year. Serum samples were analyzed for bile acid metabolites and surrogate markers of cholestasis in 4-week intervals after 1 g/d UDCA, wash-out, 0.5 g/d isoUDCA, 0.75 g/d isoUDCA, 0.75 g/d UDCA, and two further periods with 1 g/d UDCA. Bile acids in urine were analyzed after wash-out, 0.5 and 0.75 g/d isoUDCA, and 0.75 and 1 g/d UDCA. During wash-out, AST, AP, and -GT rose significantly ( P 0.05) but reversed to previous levels during the first isoUDCA period, with 0.5 g/d only. No further improvements were observed after increasing the dose of isoUDCA or switching back to UDCA. In serum, the relative amounts of isoUDCA and UDCA were 8.1 7.4% and 16.2 6.4% during 0.5 g/d isoUDCA, 6.2 2.5% and 45.0 4.1% during 0.75 g/d isoUDCA, and 0.5–3% and 56.4–60.0%, respectively, during UDCA. In urine, UDCA was the predominant bile acid both during isoUDCA and UDCA medications. The similar serum enrichment and urinary excretion of UDCA during administration of either isoUDCA or UDCA together with low concentrations of the intermediate of isomerization, 3-dehydro-UDCA, indicate a first-pass epimerization of isoUDCA to UDCA in the liver. Approximately 25% of serum isoUDCA and 10% of serum UDCA were conjugated with either glucuronic acid or N -acetylglucosamine, indicating hepatic formation and systemic secretion of glycosidic conjugates. In PBC patients, isoUDCA becomes isomerized to UDCA and has similar effects on surrogate markers of cholestasis. Thus, isoUDCA has pro-drug characteristics. —Marschall, H-U., U. Broomé, C. Einarsson, G. Alvelius, H. G. Thomas, and S. Matern. I soursodeoxycholic acid: metabolism and therapeutic effects in primary biliary cirrhosis. J. Lipid Res. 2001. 42: 735–742. Supplementary key words ursodeoxycholic acid • bile acid metabolis • N -acetylglucosaminidation • glucosidation • glucuronidation • gas chromatography-mass spectrometry • electrospray mass spectrometry Ursodeoxycholic acid (UDCA) improves clinical and biochemical indices in a variety of cholestatic liver diseases (1). UDCA is now considered as the first line treatment option for patients with primary biliary cirrhosis (PBC), since the results from the combined analysis of the three largest randomized clinical trials of UDCA in PBC indicate that UDCA improves survival free of liver transplantation (2). The validity of this finding has, however, recently been questioned (3). The mechanisms of action of UDCA are still under debate. There is evidence that the hydrophilic UDCA protects against injury of bile ducts by hydrophobic bile acids and stimulates the excretion of these and other potentially hepatotoxic compounds (1). One of the major metabolites of orally administered UDCA is the 3 -hydroxy epimer, isoursodeoxycholic acid (isoUDCA) (4–10), mostly likely formed in the intestine by bacterial enzymes (8). IsoUDCA and UDCA have very similar hydrophilicity (11) and are excreted in urine mainly as 7 N -acetylglucosamine conjugates (11–16). We found isoUDCA in vitro to be even more cytoprotective than UDCA against ethanol-induced cell injuries in HepG2 cells (15). We assumed from the chemical and cytroprotective properties that isoUDCA could be pharmacologically active in cholestatic liver disease. After our previous study of the metabolism of isoUDCA in healthy humans (15), we now present the data of a pilot study with isoUDCA in patients with PBC. We investigated whether the metabolism of isoUDCA might be altered in cholestasis and whether isoUDCA would have a pharmacodynamic effect comparable to UDCA. Abbreviations: CA, cholic acid; CDCA, chenodeoxycholic acid; LCA, lithocholic adid; GLC, gas-liquid chromatography; GC-MS, gas chromatography-mass spectrometry; ES-MS, electrospray-mass spectrometry; Glc, glucose; GlcA, glucuronic acid; GlcNAc, N -acetylglucosamine; isoUDCA, isoursodeoxycholic acid; UDCA, ursodeoxycholic acid. 1 Preliminary data of this study were presented (and published in abstract forms) at the EASL meeting, April 1999, Naples, Italy ( J. Hepatol. 1999. 30: Suppl. 1 , 144) and at the DDW, May 1999, Orlando, Florida, USA ( Gastroenterology. 1999. 116: G0086). 2 To whom correspondence should be addressed. e-mail: [email protected] by gest, on A uust 8, 2017 w w w .j.org D ow nladed fom