El Masri Ali El Rida, Tobler Caroline, Willemijn Breunis, Von Bueren Andre O, Ansari Marc, Samer Caroline Flora
Division of Clinical Pharmacology and Toxicology, Department of Anaesthesiology, Pharmacology, Intensive Care and Emergency Medicine, Geneva University Hospitals, Geneva, Switzerland.
Division of Pediatric Oncology and Hematology, Department of Women, Child and Adolescent, University Geneva Hospitals, Geneva, Switzerland.
Front Pharmacol. 2023 May 2;14:1130548. doi: 10.3389/fphar.2023.1130548. eCollection 2023.
Methotrexate is an immunosuppressant and chemotherapeutic agent used in the treatment of a range of autoimmune disorders and cancers. Its main serious adverse effects, bone marrow suppression and gastrointestinal complications, arise from its antimetabolite effect. Nevertheless, hepatotoxicity and nephrotoxicity are two widely described adverse effects of methotrexate. Its hepatotoxicity has been studied mainly in the low-dose, chronic setting, where patients are at risk of fibrosis/cirrhosis. Studies of acute hepatoxicity of high dose methotrexate, such as during chemotherapy, are scarce. We present the case of a 14-year-old patient who received high-dose methotrexate and subsequently developed acute fulminant liver failure and acute kidney injury. Genotyping of (Methylene tetrahydrofolate reductase gene), (codes for P-glycoprotein, intestinal transport and biliary excretion), (codes for BCRP, intestinal transporter and renal excretion) and (codes for OATP1B1, hepatic transporter) identified variants in all the genes analysed that predicted a reduced rate of methotrexate elimination and thus may have contributed to the clinical situation of the patient. Precision medicine involving pharmacogenomic testing could potentially avoid such adverse drug effects.
甲氨蝶呤是一种免疫抑制剂和化疗药物，用于治疗一系列自身免疫性疾病和癌症。其主要的严重不良反应，即骨髓抑制和胃肠道并发症，源于其抗代谢作用。然而，肝毒性和肾毒性是甲氨蝶呤两种被广泛描述的不良反应。其肝毒性主要在低剂量、慢性情况下进行研究，在此情况下患者有发生纤维化/肝硬化的风险。关于高剂量甲氨蝶呤急性肝毒性的研究，如在化疗期间，较为稀少。我们报告一例14岁患者，其接受高剂量甲氨蝶呤治疗后继而发生急性暴发性肝衰竭和急性肾损伤。对亚甲基四氢叶酸还原酶基因、编码P-糖蛋白（参与肠道转运和胆汁排泄）的基因、编码乳腺癌耐药蛋白（参与肠道转运和肾脏排泄）的基因以及编码有机阴离子转运多肽1B1（肝脏转运体）的基因进行基因分型，结果发现在所有分析的基因中均存在变异，这些变异预示甲氨蝶呤清除率降低，因此可能导致了该患者的临床情况。涉及药物基因组学检测的精准医学有可能避免此类药物不良反应。
