Title: The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: A potential mechanism for hepatic adverse reactions
Abstract: Clinical Pharmacology & TherapeuticsVolume 69, Issue 4 p. 223-231 Pharmacodynamics and Drug Action The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: A potential mechanism for hepatic adverse reactions Karin Fattinger MD, Corresponding Author Karin Fattinger MD Division of Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital, Zurich, Ltd, Zürich Non-Clinical Development-Drug Safety, Pharmaceuticals Division, and Clinical Science, F. Hoffmann–La Roche, Zurich, Ltd, Basel Department of Clinical Pharmacology, University of Berne, Berne, SwitzerlandDivision of Clinical Pharmacology and Toxicology, Dept of Medicine, University Hospital, CH-8091 Zürich, Switzerland. E-mail: [email protected]Search for more papers by this authorChristoph Funk PhD, Christoph Funk PhD Division of Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital, Zurich, Ltd, Zürich Non-Clinical Development-Drug Safety, Pharmaceuticals Division, and Clinical Science, F. Hoffmann–La Roche, Zurich, Ltd, Basel Department of Clinical Pharmacology, University of Berne, Berne, SwitzerlandSearch for more papers by this authorMichael Pantze PhD, Michael Pantze PhD Division of Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital, Zurich, Ltd, Zürich Non-Clinical Development-Drug Safety, Pharmaceuticals Division, and Clinical Science, F. Hoffmann–La Roche, Zurich, Ltd, Basel Department of Clinical Pharmacology, University of Berne, Berne, SwitzerlandSearch for more papers by this authorCornelia Weber PhD, Cornelia Weber PhD Division of Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital, Zurich, Ltd, Zürich Non-Clinical Development-Drug Safety, Pharmaceuticals Division, and Clinical Science, F. Hoffmann–La Roche, Zurich, Ltd, Basel Department of Clinical Pharmacology, University of Berne, Berne, SwitzerlandSearch for more papers by this authorJürg Reichen MD, Jürg Reichen MD Division of Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital, Zurich, Ltd, Zürich Non-Clinical Development-Drug Safety, Pharmaceuticals Division, and Clinical Science, F. Hoffmann–La Roche, Zurich, Ltd, Basel Department of Clinical Pharmacology, University of Berne, Berne, SwitzerlandSearch for more papers by this authorBruno Stieger PhD, Bruno Stieger PhD Division of Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital, Zurich, Ltd, Zürich Non-Clinical Development-Drug Safety, Pharmaceuticals Division, and Clinical Science, F. Hoffmann–La Roche, Zurich, Ltd, Basel Department of Clinical Pharmacology, University of Berne, Berne, SwitzerlandSearch for more papers by this authorPeter J. Meier MD, Peter J. Meier MD Division of Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital, Zurich, Ltd, Zürich Non-Clinical Development-Drug Safety, Pharmaceuticals Division, and Clinical Science, F. Hoffmann–La Roche, Zurich, Ltd, Basel Department of Clinical Pharmacology, University of Berne, Berne, SwitzerlandSearch for more papers by this author Karin Fattinger MD, Corresponding Author Karin Fattinger MD Division of Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital, Zurich, Ltd, Zürich Non-Clinical Development-Drug Safety, Pharmaceuticals Division, and Clinical Science, F. Hoffmann–La Roche, Zurich, Ltd, Basel Department of Clinical Pharmacology, University of Berne, Berne, SwitzerlandDivision of Clinical Pharmacology and Toxicology, Dept of Medicine, University Hospital, CH-8091 Zürich, Switzerland. E-mail: [email protected]Search for more papers by this authorChristoph Funk PhD, Christoph Funk PhD Division of Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital, Zurich, Ltd, Zürich Non-Clinical Development-Drug Safety, Pharmaceuticals Division, and Clinical Science, F. Hoffmann–La Roche, Zurich, Ltd, Basel Department of Clinical Pharmacology, University of Berne, Berne, SwitzerlandSearch for more papers by this authorMichael Pantze PhD, Michael Pantze PhD Division of Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital, Zurich, Ltd, Zürich Non-Clinical Development-Drug Safety, Pharmaceuticals Division, and Clinical Science, F. Hoffmann–La Roche, Zurich, Ltd, Basel Department of Clinical Pharmacology, University of Berne, Berne, SwitzerlandSearch for more papers by this authorCornelia Weber PhD, Cornelia Weber PhD Division of Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital, Zurich, Ltd, Zürich Non-Clinical Development-Drug Safety, Pharmaceuticals Division, and Clinical Science, F. Hoffmann–La Roche, Zurich, Ltd, Basel Department of Clinical Pharmacology, University of Berne, Berne, SwitzerlandSearch for more papers by this authorJürg Reichen MD, Jürg Reichen MD Division of Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital, Zurich, Ltd, Zürich Non-Clinical Development-Drug Safety, Pharmaceuticals Division, and Clinical Science, F. Hoffmann–La Roche, Zurich, Ltd, Basel Department of Clinical Pharmacology, University of Berne, Berne, SwitzerlandSearch for more papers by this authorBruno Stieger PhD, Bruno Stieger PhD Division of Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital, Zurich, Ltd, Zürich Non-Clinical Development-Drug Safety, Pharmaceuticals Division, and Clinical Science, F. Hoffmann–La Roche, Zurich, Ltd, Basel Department of Clinical Pharmacology, University of Berne, Berne, SwitzerlandSearch for more papers by this authorPeter J. Meier MD, Peter J. Meier MD Division of Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital, Zurich, Ltd, Zürich Non-Clinical Development-Drug Safety, Pharmaceuticals Division, and Clinical Science, F. Hoffmann–La Roche, Zurich, Ltd, Basel Department of Clinical Pharmacology, University of Berne, Berne, SwitzerlandSearch for more papers by this author First published: 02 April 2001 https://doi.org/10.1067/mcp.2001.114667Citations: 70Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Abstract Background During clinical trials bosentan, the first orally active endothelin receptor antagonist, caused asymptomatic transaminase elevations in some patients. In this study we investigated whether inhibition of the hepatocanalicular bile salt export pump (rodents, Bsep; humans, BSEP ABCB11) could account for bosentan-induced liver injury. Methods We reanalyzed the safety database of the bosentan trials for cholestatic liver injury, determined the cholestatic potency of bosentan in the rat, and studied the effects of bosentan and its metabolites on Bsep-mediated taurocholate transport in vitro. Results Bosentan caused dose-dependent and reversible liver injury in 2% to 18% of patients and caused a significant increase of serum bile salt levels (P < .01). Concomitant administration of glyburide (INN, glibenclamide) enhanced the cholestatic potency of bosentan. Similar effects were seen in rats, in which serum bile salt levels were increased by glyburide less than by bosentan, which increased the levels less than a combination of bosentan and glyburide. In vitro, Bsep-mediated taurocholate transport was inhibited by bosentan (inhibition constant, ≈12 μmol/L) and metabolites (inhibition constant, ≈8.5 μmol/L for metabolite Ro 47–8634). Conclusion These results indicate that bosentan-induced liver injury is mediated, at least in part, by inhibition of Bsep/BSEP–causing intracellular accumulation of cytotoxic bile salts and bile salt induced liver cell damage. The data further emphasize the pathophysiologic importance of drug-Bsep interactions in acquired forms of cholestatic liver injury. Clinical Pharmacology & Therapeutics (2001) 69, 223–231; doi: 10.1067/mcp.2001.114667 References 1Benigni, A. and Remuzzi, G. (1999). Endothelin antagonists. 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Publication Year: 2001
Publication Date: 2001-04-01
Language: en
Type: article
Indexed In: ['crossref', 'pubmed']
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Cited By Count: 486
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