{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T11:15:12Z","timestamp":1791976512577,"version":"4.4.0"},"reference-count":25,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,10,18]],"date-time":"2022-10-18T00:00:00Z","timestamp":1666051200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,10,18]],"date-time":"2022-10-18T00:00:00Z","timestamp":1666051200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Med Case Reports"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Pulmonary arterial hypertension is a progressive, debilitating condition characterized by increased resistance in the pulmonary arterial circulation. Current treatments for pulmonary arterial hypertension include endothelin receptor antagonists such as bosentan, sitaxentan, ambrisentan, macitentan, and oral prostacyclin receptor agonists such as selexipag. Endothelin receptor antagonists have been associated with liver injury, while hepatotoxicity was not reported for selexipag. Although genetic variability has been indisputably associated with variability in drug response, no study has been designed until now to assess its effects on the pharmacokinetics of endothelin receptor antagonists or selexipag.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Case presentation<\/jats:title>\n                <jats:p>We report the case of a 58-year-old female Caucasian patient with a dramatic increase in plasma levels of transaminases after treatment with macitentan and selexipag, drugs whose risk of causing liver injury has so far been considered limited. After therapy discontinuation, plasma levels of transaminases returned to baseline, thus suggesting a role of these drugs in the observed hepatotoxicity. After pharmacological counseling, we decided to introduce ambrisentan for the patient\u2019s treatment. After 7 months of treatment, no liver injury has been reported. To evaluate the role of genetic factors in the observed hepatotoxicity, we genotyped the patient for single-nucleotide polymorphisms previously associated with macitentan, ambrisentan, or selexipag metabolism. We found a genetic profile associated with a poor metabolizer (PM) phenotype for <jats:italic>CYP2C8<\/jats:italic> and <jats:italic>CYP2C9<\/jats:italic>, key enzymes for elimination of both macitentan and selexipag. The reported results suggest that an allelic profile associated with low activity for <jats:italic>CYP2C8<\/jats:italic> and <jats:italic>CYP2C9<\/jats:italic> enzyme could be a potential risk factor for macitentan and selexipag-induced liver injury and could provide a possible marker for early identification of subjects at higher risk of developing hepatotoxicity.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>A multidisciplinary approach based on clinical evaluation, as well as pharmacological counseling and evaluation of the patient\u2019s genetic profile, might be useful for identification of patients with a high chance of drug-induced liver injury, avoiding unnecessary risks in therapy selection and prescription.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13256-022-03571-9","type":"journal-article","created":{"date-parts":[[2022,10,18]],"date-time":"2022-10-18T09:03:15Z","timestamp":1666083795000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Pharmacological counseling in hepatotoxicity induced by macitentan and selexipag: \u00a0a case report\u00a0"],"prefix":"10.1186","volume":"16","author":[{"given":"Mariangela","family":"Lattanzio","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2986-1272","authenticated-orcid":false,"given":"Marco","family":"Ferrari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Martini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Ceriani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Imporzani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franca","family":"Marino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"De Ponti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Cosentino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,10,18]]},"reference":[{"key":"3571_CR1","doi-asserted-by":"publisher","first-page":"1573","DOI":"10.1016\/j.jacc.2009.01.004","volume":"53","author":"VV McLaughlin","year":"2009","unstructured":"McLaughlin VV, Archer SL, Badesch DB, et al. American College of Cardiology Foundation Task Force on Expert Consensus Documents; American Heart Association; American College of Chest Physicians; American Thoracic Society, Inc; Pulmonary Hypertension Association. ACCF\/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009;53:1573\u2013619.","journal-title":"J Am Coll Cardiol."},{"key":"3571_CR2","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1183\/09031936.00138706","volume":"30","author":"M Humbert","year":"2007","unstructured":"Humbert M, Segal ES, Kiely DG, et al. Results of European post-marketing surveillance of bosentan in pulmonary hypertension. 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