Document Detail

Influence of Verapamil and Cyclosporin A on bile acid metabolism and transport in rat liver slices.
MedLine Citation:
PMID:  16793245     Owner:  NLM     Status:  MEDLINE    
Verapamil (V) is a specific inhibitor of the P-glycoprotein (mdr1) in the hepatocyte canalicular membrane. Cyclosporin A (CsA) as an essential immunosuppressive drug has potentially cholestatic adverse effects on the liver, but increases the expression of mdr1. In precision-cut liver slices from 34- to 40-day-old male Wistar rats 26 individual free and conjugated bile acids (BAs) as markers of hepatic transport and synthesis function were analysed after 4 h incubation with V (100 microM) or CsA (5 microM) in Krebs-Henseleit buffer. Some slices were loaded with cholic acid (CA 5 microM) or tauro-ursodeoxycholic acid (T-UDCA 5 microM) to investigate the V and CsA effects under conditions of BA supplementation. BAs were determined in tissue and medium by HPLC with postcolumn derivatisation and fluorescence detection. V and CsA, influencing different targets in BA transport, enhanced slice concentrations of T- and glyco- (G-) conjugated CA only when exogenous CA was given additionally. This BA accumulation in tissue is more reflected at decreased medium concentrations of these BAs after V and CsA incubations. Both V and CsA also inhibited CA uptake into the slices. The acidic chenodeoxycholic acid (CDCA) synthesis pathway is disturbed: T- and G-CDCA concentrations are diminished in slices and medium after V and CsA incubations. T-UDCA plus V or CsA enhanced not only its own slice concentration but also the concentration of the trihydroxylated tauro-muricholic acid (T-beta-MCA), reflecting the conversion of the accumulated dihydroxylated T-UDCA into the T-beta-MCA. The similar effects of V and CsA on BA transport and metabolism can be explained by mdr1 mediated disturbances of cellular ATP transport rather than by inhibition of individual BA transporters.
Astrid Barth; Jerome Braun; Dieter Müller
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Publication Detail:
Type:  In Vitro; Journal Article     Date:  2006-06-21
Journal Detail:
Title:  Experimental and toxicologic pathology : official journal of the Gesellschaft für Toxikologische Pathologie     Volume:  58     ISSN:  0940-2993     ISO Abbreviation:  Exp. Toxicol. Pathol.     Publication Date:  2006 Aug 
Date Detail:
Created Date:  2006-07-28     Completed Date:  2006-09-26     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9208920     Medline TA:  Exp Toxicol Pathol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  31-7     Citation Subset:  IM    
Institute of Pharmacology and Toxicology, Friedrich Schiller University Jena, D-07740 Jena, Germany.
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MeSH Terms
Animals, Outbred Strains
Biological Transport / drug effects
Cholic Acids / analysis,  metabolism*,  pharmacology
Chromatography, High Pressure Liquid
Cyclosporine / pharmacology*
Drug Combinations
Liver / chemistry,  drug effects*,  metabolism
Rats, Wistar
Taurochenodeoxycholic Acid / analysis,  metabolism*,  pharmacology
Verapamil / pharmacology*
Reg. No./Substance:
0/Cholic Acids; 0/Drug Combinations; 516-35-8/Taurochenodeoxycholic Acid; 52-53-9/Verapamil; 59865-13-3/Cyclosporine

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