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Research ArticleToxicology

Macitentan Does Not Interfere with Hepatic Bile Salt Transport

Alexander Treiber, Päivi Äänismaa, Ruben de Kanter, Stephane Delahaye, Marianne Treher, Patrick Hess and Patricia Sidharta
Journal of Pharmacology and Experimental Therapeutics July 2014, 350 (1) 130-143; DOI: https://doi.org/10.1124/jpet.114.214106
Alexander Treiber
Departments of Preclinical Drug Metabolism and Pharmacokinetics (A.T., P.A., R.d.K., S.D.), Toxicology (M.T.), Pharmacology (P.H.), and Clinical Pharmacology (P.S.), Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
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Päivi Äänismaa
Departments of Preclinical Drug Metabolism and Pharmacokinetics (A.T., P.A., R.d.K., S.D.), Toxicology (M.T.), Pharmacology (P.H.), and Clinical Pharmacology (P.S.), Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
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Ruben de Kanter
Departments of Preclinical Drug Metabolism and Pharmacokinetics (A.T., P.A., R.d.K., S.D.), Toxicology (M.T.), Pharmacology (P.H.), and Clinical Pharmacology (P.S.), Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
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Stephane Delahaye
Departments of Preclinical Drug Metabolism and Pharmacokinetics (A.T., P.A., R.d.K., S.D.), Toxicology (M.T.), Pharmacology (P.H.), and Clinical Pharmacology (P.S.), Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
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Marianne Treher
Departments of Preclinical Drug Metabolism and Pharmacokinetics (A.T., P.A., R.d.K., S.D.), Toxicology (M.T.), Pharmacology (P.H.), and Clinical Pharmacology (P.S.), Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
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Patrick Hess
Departments of Preclinical Drug Metabolism and Pharmacokinetics (A.T., P.A., R.d.K., S.D.), Toxicology (M.T.), Pharmacology (P.H.), and Clinical Pharmacology (P.S.), Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
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Patricia Sidharta
Departments of Preclinical Drug Metabolism and Pharmacokinetics (A.T., P.A., R.d.K., S.D.), Toxicology (M.T.), Pharmacology (P.H.), and Clinical Pharmacology (P.S.), Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
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Abstract

Treatment of pulmonary arterial hypertension with the endothelin receptor antagonist bosentan has been associated with transient increases in liver transaminases. Mechanistically, bosentan inhibits the bile salt export pump (BSEP) leading to an intrahepatic accumulation of cytotoxic bile salts, which eventually results in hepatocellular damage. BSEP inhibition by bosentan is amplified by its accumulation in the liver as bosentan is a substrate of organic anion-transporting polypeptide (OATP) transport proteins. The novel endothelin receptor antagonist macitentan shows a superior liver safety profile. Introduction of the less acidic sulfamide moiety and increased lipophilicity yield a hepatic disposition profile different from other endothelin receptor antagonists. Passive diffusion rather than OATP-mediated uptake is the driving force for macitentan uptake into the liver. Interaction with the sodium taurocholate cotransporting polypeptide and BSEP transport proteins involved in hepatic bile salt homeostasis is therefore limited due to the low intrahepatic drug concentrations. Evidence for this conclusion is provided by in vitro experiments in drug transporter-expressing cell lines, acute and long-term studies in rats and dogs, absence of plasma bile salt changes in healthy human volunteers after multiple dosing, and finally the liver safety profile of macitentan in the completed phase III morbidity/mortality SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome) trial.

Footnotes

    • Received February 19, 2014.
    • Accepted April 23, 2014.
  • dx.doi.org/10.1124/jpet.114.214106.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 350 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 350, Issue 1
1 Jul 2014
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Research ArticleToxicology

Macitentan and Hepatic Bile Salt Transport

Alexander Treiber, Päivi Äänismaa, Ruben de Kanter, Stephane Delahaye, Marianne Treher, Patrick Hess and Patricia Sidharta
Journal of Pharmacology and Experimental Therapeutics July 1, 2014, 350 (1) 130-143; DOI: https://doi.org/10.1124/jpet.114.214106

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Research ArticleToxicology

Macitentan and Hepatic Bile Salt Transport

Alexander Treiber, Päivi Äänismaa, Ruben de Kanter, Stephane Delahaye, Marianne Treher, Patrick Hess and Patricia Sidharta
Journal of Pharmacology and Experimental Therapeutics July 1, 2014, 350 (1) 130-143; DOI: https://doi.org/10.1124/jpet.114.214106
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