Lennard L, Davies H A, Lilleyman J S
University of Sheffield Department of Medicine, Royal Hallamshire Hospital, UK.
Br J Cancer. 1993 Jul;68(1):186-90. doi: 10.1038/bjc.1993.311.
The cytotoxic activity of 6-mercaptopurine (6-MP) is affected by thiopurine methyltransferase (TPMT), a genetically regulated and variable intracellular enzyme. 6-Thioguanine (6-TG), a closely related thiopurine, is less affected by that enzyme and so it may be a more reliable drug-at least for patients with constitutionally high TPMT activity. We attempted to assess its suitability as an alternative by comparing the pharmacokinetics of both drugs in a small group of children with lymphoblastic leukaemia (ALL). Patients were included who were in their second or subsequent remission, who would otherwise have received 6-MP, and on whom pharmacokinetic data concerning 6-MP metabolism had been collected in a previous remission. Plasma 6-TG concentrations were assayed following an oral dose of 40 mg m-2, and the accumulation and fluctuation of intracellular (erythrocyte, RBC) 6-TG nucleotides (6-TGNs) were measured at regular intervals during daily oral therapy. Seven children were studied. Plasma 6-TG concentrations were low and cleared within 6 h of oral dosing. At 7 days, 6-TGN concentrations ranged from 959 to 2361 pmol 8 x 10(-8) RBCs, in all cases significantly higher (P = 0.002) than those produced by the same patients on 6-MP. After a total therapy time of 35 patient months, a modest rise of alanine aminotransferase was seen on one occasion, otherwise no toxicity apart from myelosuppression was encountered. In the context used, 6-TG appears well tolerated and produces higher concentrations of intracellular cytotoxic metabolites than 6-MP. For children constitutionally 'resistant' to the traditional drug, if not all, it may be a preferable alternative.
6-巯基嘌呤（6-MP）的细胞毒性活性受硫嘌呤甲基转移酶（TPMT）影响，TPMT是一种受基因调控且具有个体差异的细胞内酶。6-硫鸟嘌呤（6-TG）是一种与之密切相关的硫嘌呤，受该酶的影响较小，因此它可能是一种更可靠的药物——至少对于先天性TPMT活性较高的患者来说是这样。我们试图通过比较一小群淋巴细胞白血病（ALL）儿童中两种药物的药代动力学，来评估6-TG作为替代药物的适用性。纳入的患者为处于第二次或后续缓解期的患者，这些患者原本会接受6-MP治疗，并且在之前的缓解期已收集到有关6-MP代谢的药代动力学数据。口服40 mg m-2剂量后测定血浆6-TG浓度，并在每日口服治疗期间定期测量细胞内（红细胞，RBC）6-TG核苷酸（6-TGNs）的蓄积和波动情况。对7名儿童进行了研究。口服给药后6小时内血浆6-TG浓度较低且清除。在第7天时，6-TGN浓度范围为959至2361 pmol 8×10（-8）RBCs，在所有情况下均显著高于（P = 0.002）同一患者使用6-MP时产生的浓度。在35个患者月的总治疗时间后，有一次观察到丙氨酸转氨酶略有升高，除此之外，除了骨髓抑制外未遇到其他毒性。在本研究背景下，6-TG似乎耐受性良好，并且比6-MP产生更高浓度的细胞内细胞毒性代谢产物。对于对传统药物“耐药”的儿童（如果不是全部），它可能是一种更可取的替代药物。
