Predictive model of bosentan-induced liver toxicity in Japanese patients with pulmonary arterial hypertension
Predictive model of bosentan-induced liver toxicity in Japanese patients with pulmonary arterial hypertension
复制标题
日本肺动脉高压患者波生坦所致肝毒性的预测模型
DOI：
10.1139/cjpp-2019-0656
复制
发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Noriaki Emoto
中科院分区：
文献类型：
--
作者：
Kennosuke Yorifuji;Yuko Uemura;Shinji Horibata;Goh Tsuji;Yoko Suzuki;Kazuhiko Nakayama;Takashi Hatae;Shunichi Kumagai;Noriaki Emoto
波生坦是一种内皮素受体拮抗剂，已被广泛用作治疗肺动脉高压(PAH)的一线药物。它已被证明可以改善高血压症状、运动能力和血流动力学，并延长临床恶化的时间。然而，肝功能障碍是波生坦治疗的一个主要副作用，可能会阻碍对PAH患者的最佳治疗。此前，我们使用药物代谢酶和转运体分析证明，在波生坦治疗期间氨基转移酶升高的患者中，碳水化合物磺基转移酶3(CHST3)和CHST13等位基因的频率显著高于没有肝脏毒性的患者。此外，我们使用两个单核苷酸多态和两个非遗传因素构建了一个药物基因组学模型来预测波生坦引起的PAH患者的肝损伤。本研究的目的是在外部验证波生坦对日本患者的肝毒性的预测模型。我们评估了5例接受波生坦治疗的患者，其中1例出现肝功能障碍。我们将CHST3和CHST13的突变等位基因、血肌酐和年龄应用到我们的模型中来预测肝功能障碍。敏感度为100%，特异度为50%。考虑到PAH是一种罕见的疾病，需要多中心协作来验证我们的模型。
Bosentan, an endothelin receptor antagonist, has been widely used as a first-line medication for the treatment of pulmonary arterial hypertension (PAH). It has been shown to improve symptoms of hypertension, exercise capacity, and hemodynamics and prolong time to clinical worsening. However, liver dysfunction is a major side effect of bosentan treatment that could hamper the optimal management of patients with PAH. Previously, we demonstrated, using drug metabolism enzymes and transporters analysis, that the carbohydrate sulfotransferase 3 (CHST3) andCHST13alleles are significantly more frequent in patients with elevated aminotransferases during therapy with bosentan than they are in patients without liver toxicity. In addition, we constructed a pharmacogenomics model to predict bosentan-induced liver injury in patients with PAH using two single-nucleotide polymorphisms and two nongenetic factors. The purpose of the present study was to externally validate the predictive model of bosentan-induced liver toxicity in Japanese patients. We evaluated five cases of patients treated with bosentan, and one presented with liver dysfunction. We applied mutation alleles ofCHST3andCHST13, serum creatinine, and age to our model to predict liver dysfunction. The sensitivity and specificity were calculated as 100% and 50%, respectively. Considering that PAH is a rare disease, multicenter collaboration would be necessary to validate our model.