Mei Shenghui, Li Xindi, Gong Xiaoqing, Zhang Xiaoyi, Li Xingang, Yang Li, Zhu Leting, Zhou Heng, Liu Yonghong, Zhou Anna, Zhang Xinghu, Zhao Zhigang
Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing, People's Republic of China.
Department of Clinical Pharmacology, College of Pharmaceutical Sciences, Capital Medical University, Beijing, People's Republic of China.
Biomed Chromatogr. 2017 Sep;31(9). doi: 10.1002/bmc.3959. Epub 2017 Mar 29.
Thiopurines (TPDs) are first-line drugs in treating neuromyelitis optica spectrum disorders (NMOSD). Evaluation of thiopurine S-methyltransferase activity (TPMT), a major determinant of TPD toxicity, before TPD treatment using 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) as substrate was suggested. However, the equivalent of the two substrates in TPMT activity evaluation was unknown, and an alternative substrate was required in TPMT activity evaluation in patients who were already taking 6-MP or 6-TG. Before evaluating the agreement of 6-MP and 6-TG in TPMT activity measurement in patients with NMOSD, the affinity of the two substrates for the active center of TPMT should be established. A computer-based simulation indicated that 6-MP and 6-TG had similar affinities for the two active sites of TPMT. According to the guidelines, an LC-MS/MS method was developed and validated to evaluate the TPMT activity in human erythrocyte hemolysate using 6-MP or 6-TG as substrates via 1 h incubation at 37°C. The method was applied in 81 patients with NMOSD. Evaluated by Bland-Altman plot, 6-methylmercaptopurine and 6-methylthioguanine represented TPMT activities were in agreement with each other. Further studies are warranted to confirm the results.
硫嘌呤类药物（TPDs）是治疗视神经脊髓炎谱系障碍（NMOSD）的一线药物。建议在使用6-巯基嘌呤（6-MP）和6-硫鸟嘌呤（6-TG）作为底物进行TPD治疗前，评估硫嘌呤甲基转移酶活性（TPMT），这是TPD毒性的主要决定因素。然而，在TPMT活性评估中这两种底物的等效性尚不清楚，对于已经在服用6-MP或6-TG的患者，TPMT活性评估需要一种替代底物。在评估NMOSD患者TPMT活性测量中6-MP和6-TG的一致性之前，应确定这两种底物对TPMT活性中心的亲和力。基于计算机的模拟表明，6-MP和6-TG对TPMT的两个活性位点具有相似的亲和力。根据指南，开发并验证了一种液相色谱-串联质谱法（LC-MS/MS），以6-MP或6-TG作为底物，在37°C孵育1小时，评估人红细胞溶血产物中的TPMT活性。该方法应用于81例NMOSD患者。通过Bland-Altman图评估，6-甲基巯基嘌呤和6-甲基硫鸟嘌呤所代表的TPMT活性彼此一致。需要进一步研究以证实该结果。
