Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.
Aliment Pharmacol Ther. 2020 Jun;51(12):1286-1304. doi: 10.1111/apt.15743. Epub 2020 May 3.
Thiopurines in combination with glucocorticoids are used as first-line, second-line and maintenance therapies in autoimmune hepatitis and opportunities exist to improve and expand their use.
To describe the metabolic pathways and key factors implicated in the efficacy and toxicity of the thiopurine drugs and to indicate the opportunities to improve outcomes by monitoring and manipulating metabolic pathways, individualising dosage and strengthening the response.
English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed.
Thiopurine methyltransferase activity and 6-tioguanine (6-thioguanine) nucleotide levels influence drug efficacy and safety, and they can be manipulated to improve treatment response and prevent myelosuppression. Methylated thiopurine metabolites are associated with hepatotoxicity, drug intolerance and nonresponse and their production can be reduced or bypassed. Universal pre-treatment assessment of thiopurine methyltransferase activity and individualisation of dosage to manipulate metabolite thresholds could improve outcomes. Early detection of thiopurine resistance by metabolite testing, accurate estimations of drug onset and strength by surrogate markers and adjunctive use of allopurinol could improve the management of refractory disease. Dose-restricted tioguanine (thioguanine) could expand treatment options by reducing methylated metabolites, increasing the bioavailability of 6-tioguanine nucleotides and ameliorating thiopurine intolerance or resistance.
The efficacy and safety of thiopurines in autoimmune hepatitis can be improved by investigational efforts that establish monitoring strategies that allow individualisation of dosage and prediction of outcome, increase bioavailability of the active metabolites and demonstrate superiority to alternative agents.
硫唑嘌呤与糖皮质激素联合用于自身免疫性肝炎的一线、二线和维持治疗，有机会改善和扩大其应用。
描述硫唑嘌呤类药物疗效和毒性的代谢途径和关键因素，并指出通过监测和操纵代谢途径、个体化剂量和增强反应来改善结果的机会。
通过多个搜索词在 PubMed 中确定英文摘要。选择全文进行综述，并开发二级和三级参考文献。
硫嘌呤甲基转移酶活性和 6-硫代鸟嘌呤（6-TG）核苷酸水平影响药物的疗效和安全性，可以通过操纵来改善治疗反应和预防骨髓抑制。甲基化硫嘌呤代谢物与肝毒性、药物不耐受和无反应相关，其产生可以减少或绕过。普遍的硫嘌呤甲基转移酶活性预治疗评估和剂量个体化以操纵代谢物阈值可能改善结果。通过代谢物检测早期发现硫嘌呤耐药，通过替代标志物准确估计药物的起始和强度，以及辅助使用别嘌醇，可以改善难治性疾病的管理。限制剂量的硫代鸟嘌呤（硫鸟嘌呤）可以通过减少甲基化代谢物、增加 6-TG 核苷酸的生物利用度以及改善硫嘌呤不耐受或耐药性来扩大治疗选择。
通过研究努力，可以改善自身免疫性肝炎中硫唑嘌呤的疗效和安全性，这些研究努力建立了允许剂量个体化和预测结果的监测策略，增加了活性代谢物的生物利用度，并证明了优于替代药物的优势。
