Document Detail


Effect of ursodeoxycholic acid on bile acid profiles and intestinal detoxification machinery in primary biliary cirrhosis and health.
MedLine Citation:
PMID:  22414767     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND & AIMS: Ursodeoxycholic acid (UDCA) exerts anticholestatic, antifibrotic and antiproliferative effects in primary biliary cirrhosis (PBC) via mechanisms not yet fully understood. Its adequate biliary enrichment is considered mandatory for therapeutic efficacy. However, precise determination of biliary enrichment of UDCA is not possible in clinical practice. Therefore, we investigated (i) the relationship between biliary enrichment and plasma pharmacokinetics of UDCA, (ii) the effect of UDCA on plasma and biliary bile acid composition and conjugation patterns, and (iii) on the intestinal detoxification machinery in patients with PBC and healthy controls.
METHODS: In 11 PBC patients and 11 matched healthy subjects, cystic bile and duodenal tissue were collected before and after 3 weeks of administration of UDCA (15 mg/kg/day). Extensive pharmacokinetic profiling of bile acids was performed. The effect of UDCA on the intestinal detoxification machinery was studied by quantitative PCR and Western blotting.
RESULTS: The relative fraction of UDCA and its conjugates in plasma at trough level[x] correlated with their biliary enrichment[y] (r=0.73, p=0.0001, y=3.65+0.49x). Taurine conjugates of the major hydrophobic bile acid, chenodeoxycholic acid, were more prominent in bile of PBC patients than in that of healthy controls. Biliary bile acid conjugation patterns normalized after treatment with UDCA. UDCA induced duodenal expression of key export pumps, BCRP and P-glycoprotein.
CONCLUSIONS: Biliary and trough plasma enrichment of UDCA are closely correlated in PBC and health. Taurine conjugation may represent an adaptive mechanism in PBC against chenodeoxycholic acid-mediated bile duct damage. UDCA may stabilize small intestinal detoxification by upregulation of efflux pumps.
Authors:
Karin Dilger; Simon Hohenester; Ursula Winkler-Budenhofer; Barbara A J Bastiaansen; Frank G Schaap; Christian Rust; Ulrich Beuers
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Publication Detail:
Type:  Controlled Clinical Trial; Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-03-10
Journal Detail:
Title:  Journal of hepatology     Volume:  57     ISSN:  1600-0641     ISO Abbreviation:  J. Hepatol.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-06-19     Completed Date:  2012-11-05     Revised Date:  2014-04-01    
Medline Journal Info:
Nlm Unique ID:  8503886     Medline TA:  J Hepatol     Country:  England    
Other Details:
Languages:  eng     Pagination:  133-40     Citation Subset:  IM    
Copyright Information:
Copyright © 2012. Published by Elsevier B.V.
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MeSH Terms
Descriptor/Qualifier:
Adult
Bile Acids and Salts / blood*
Biliary Tract / drug effects,  metabolism
Carrier Proteins / genetics,  metabolism
Cholagogues and Choleretics / administration & dosage,  blood,  pharmacokinetics*
Cholestasis / drug therapy,  metabolism
Cytochrome P-450 CYP3A / genetics,  metabolism
Duodenum / drug effects,  metabolism
Female
Gene Expression Profiling
Glycine / blood
Humans
Intestinal Mucosa / metabolism
Liver Cirrhosis, Biliary / drug therapy*,  metabolism*
Metabolic Detoxication, Drug / physiology
Middle Aged
Taurine / blood
Ursodeoxycholic Acid / administration & dosage,  blood,  pharmacokinetics*
Chemical
Reg. No./Substance:
0/Bile Acids and Salts; 0/Carrier Proteins; 0/Cholagogues and Choleretics; 1EQV5MLY3D/Taurine; 724L30Y2QR/Ursodeoxycholic Acid; EC 1.14.13.67/CYP3A4 protein, human; EC 1.14.14.1/Cytochrome P-450 CYP3A; TE7660XO1C/Glycine
Comments/Corrections
Erratum In:
J Hepatol. 2014 Mar;60(3):684

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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