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Multiple compound-related adverse properties contribute to liver injury caused by endothelin receptor antagonists

J Gerry Kenna1, Simone H Stahl1, Julie A Eakins1

  • 1Drug Safety Consultant, Macclesfield, Cheshire, United Kingdom (J.G.K.); DMPK (S.H.S.), Discovery Safety (J.A.E.), and Translational Safety (A.J.F.), Drug Safety and Metabolism, AstraZeneca R&D Alderley Park, Macclesfield, Cheshire, United Kingdom; DMPK (L.C.A., J.B., C.S.E.), Regulatory Safety (M.B.), Drug Safety and Metabolism, AstraZeneca R&D Mölndal, Mölndal, Sweden; and DMPK, Cardiovascular and Metabolic Diseases (M.E.), and Respiratory, Inflammation, and Autoimmunity (R.A.T.), iMED AstraZeneca R&D Mölndal, Mölndal, Sweden.

The Journal of Pharmacology and Experimental Therapeutics
|December 4, 2014
PubMed

Insights

Sitaxentan and bosentan, endothelin receptor antagonists, can cause drug-induced liver injury through multiple mechanisms. Ambrisentan shows a lower risk, indicating greater safety in clinical use.

Area of Science:

  • Hepatology
  • Pharmacology
  • Drug Safety

Background:

  • Drug-induced liver injury (DILI) is a concern with endothelin receptor antagonists (ERAs).
  • Sitaxentan and bosentan have been associated with DILI, unlike ambrisentan.
  • Understanding the mechanisms of ERA-induced DILI is crucial for patient safety.

Purpose of the Study:

  • To investigate the multiple mechanisms contributing to ERA-induced liver toxicity.
  • To compare the in vitro toxicity profiles of sitaxentan, bosentan, and ambrisentan.
  • To elucidate the differential hepatotoxicity among ERAs.

Main Methods:

  • Quantification of bile salt export pump (BSEP) and multidrug resistance-associated protein 2 inhibition using membrane vesicle assays.
  • Assessment of mitochondrial respiration inhibition in HuH-7 cells via Seahorse XF(e96) analyzer.
  • Evaluation of P450-independent and P450-mediated cell toxicity in THLE cell lines.
  • Calculation of exposure-adjusted assay ratios and covalent binding (CVB) body burdens.

Main Results:

  • Sitaxentan showed positive exposure-adjusted signals in all five in vitro assays and a high CVB body burden.
  • Bosentan exhibited a positive signal in one assay (BSEP inhibition) and a moderate CVB body burden.
  • Ambrisentan displayed no positive exposure-adjusted signals and a low CVB body burden.

Conclusions:

  • Multiple mechanisms contribute to sitaxentan-induced liver injury.
  • These findings provide a rationale for the lower hepatotoxicity of bosentan compared to sitaxentan.
  • Ambrisentan demonstrates a favorable safety profile regarding drug-induced liver injury.

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