Pulmonary Hypertension Unit, Department of Heart and Vessels, Ospedale di Circolo and Fondazione Macchi, University of Insubria, Varese, Italy.
Center of Research in Medical Pharmacology, University of Insubria, Via Monte Generoso 71, 21100, Varese, Italy.
J Med Case Rep. 2022 Oct 18;16(1):385. doi: 10.1186/s13256-022-03571-9.
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.
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's 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 CYP2C8 and CYP2C9, key enzymes for elimination of both macitentan and selexipag. The reported results suggest that an allelic profile associated with low activity for CYP2C8 and CYP2C9 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.
A multidisciplinary approach based on clinical evaluation, as well as pharmacological counseling and evaluation of the patient's 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.
肺动脉高压是一种进行性、使人虚弱的疾病，其特征是肺循环中的动脉阻力增加。目前肺动脉高压的治疗方法包括内皮素受体拮抗剂，如波生坦、西他生坦、安立生坦、马西替坦和口服前列环素受体激动剂，如塞利西帕。内皮素受体拮抗剂与肝损伤有关，而塞利西帕则没有报告有肝毒性。虽然遗传变异与药物反应的变异性有明确的关联，但直到现在还没有设计研究来评估其对内皮素受体拮抗剂或塞利西帕药代动力学的影响。
我们报告了一名 58 岁的白种女性患者的病例，她在使用马西替坦和塞利西帕治疗后，血浆中转氨酶水平急剧升高，而这两种药物引起肝损伤的风险迄今被认为是有限的。停药后，血浆中转氨酶水平恢复到基线，因此提示这些药物在观察到的肝毒性中起作用。经过药理咨询，我们决定为该患者引入安立生坦进行治疗。治疗 7 个月后，未报告肝损伤。为了评估遗传因素在观察到的肝毒性中的作用，我们对该患者进行了与马西替坦、安立生坦或塞利西帕代谢相关的单核苷酸多态性基因分型。我们发现了一种与 CYP2C8 和 CYP2C9 代谢相关的不良代谢者 (PM) 表型的遗传谱，CYP2C8 和 CYP2C9 是马西替坦和塞利西帕消除的关键酶。报告的结果表明，CYP2C8 和 CYP2C9 酶活性低的等位基因谱可能是马西替坦和塞利西帕引起肝损伤的潜在危险因素，并可能为早期识别发生肝毒性风险较高的患者提供可能的标志物。
基于临床评估、药理咨询以及对患者遗传谱的评估的多学科方法可能有助于识别药物引起肝损伤的高风险患者，避免在治疗选择和处方方面带来不必要的风险。
