Document Detail

Isoursodeoxycholic acid: metabolism and therapeutic effects in primary biliary cirrhosis.
MedLine Citation:
PMID:  11352980     Owner:  NLM     Status:  MEDLINE    
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 gamma-glutamyl transpeptidase (gamma-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 gamma-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.
H U Marschall; U Broomé; C Einarsson; G Alvelius; H G Thomas; S Matern
Publication Detail:
Type:  Clinical Trial; Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of lipid research     Volume:  42     ISSN:  0022-2275     ISO Abbreviation:  J. Lipid Res.     Publication Date:  2001 May 
Date Detail:
Created Date:  2001-05-15     Completed Date:  2001-08-30     Revised Date:  2009-11-03    
Medline Journal Info:
Nlm Unique ID:  0376606     Medline TA:  J Lipid Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  735-42     Citation Subset:  IM    
Karolinska Institutet, Department of Medicine, Division of Gastroenterology and Hepatology, and Clinical Research Center at NOVUM, Huddinge University Hospital, K63, S-141 86 Stockholm, Sweden.
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MeSH Terms
Bile Acids and Salts / blood,  urine
Bilirubin / blood
Gas Chromatography-Mass Spectrometry
Liver / enzymology,  metabolism*
Liver Cirrhosis, Biliary / drug therapy,  metabolism*
Middle Aged
Pilot Projects
Spectrometry, Mass, Electrospray Ionization
Ursodeoxycholic Acid / analogs & derivatives*,  metabolism*,  therapeutic use
Reg. No./Substance:
0/Bile Acids and Salts; 0/Prodrugs; 128-13-2/Ursodeoxycholic Acid; 635-65-4/Bilirubin; 78919-26-3/isoursodeoxycholic acid

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