Winograd B, Lippens R J, Oosterbaan M J, Dirks M J, Vree T B, van der Kleijn E
Eur J Clin Pharmacol. 1986;30(2):231-8. doi: 10.1007/BF00614310.
In children with lymphoid malignancies 18 courses of methotrexate (18-200 mg/kg) administered as a 24-h infusion were monitored. Plasma concentrations and renal excretion rates of methotrexate (MTX) and 7-hydroxymethotrexate (7-OHMTX) were determined. A low correlation was found between the administered dose of MTX and the body exposure to MTX or 7-OHMTX. Although 84% of the MTX eventually recovered from the urine was excreted during the 24 h of the infusion, the renal clearance of MTX was markedly lower during the time of the infusion than after it. There were courses with a low and others with a high renal clearance of MTX during the infusion, despite the same urine flow. A low MTX renal clearance was correlated with a high body exposure to MTX. As the same variations were also seen in the same patient during successive courses, pharmacokinetical characterization of patients appears questionable. The renal clearance of 7-OHMTX was significantly lower than the renal clearance of MTX, and the body exposure to 7-OHMTX ranged from 2-40% of the MTX body exposure. Treatment courses with a low or a high body exposure to 7-OHMTX were not associated with different urinary recoveries of the metabolite. Differences in MTX hydroxylation could not be substantiated. Because the concentration of 7-OHMTX is high soon after the end of an infusion, a specific method of MTX determination should be chosen for controlling treatment.
对患有淋巴系统恶性肿瘤的儿童，监测了以24小时输注方式给予的18个疗程甲氨蝶呤（18 - 200mg/kg）。测定了甲氨蝶呤（MTX）和7 - 羟基甲氨蝶呤（7 - OHMTX）的血浆浓度及肾脏排泄率。发现给予的MTX剂量与MTX或7 - OHMTX的体内暴露量之间相关性较低。尽管最终从尿液中回收的MTX有84%在输注的24小时内排出，但输注期间MTX的肾脏清除率明显低于输注后。尽管尿流相同，但输注期间存在MTX肾脏清除率低的疗程和高的疗程。MTX肾脏清除率低与MTX的高体内暴露量相关。由于在同一患者的连续疗程中也观察到相同的变化，患者的药代动力学特征似乎存在疑问。7 - OHMTX的肾脏清除率显著低于MTX的肾脏清除率，7 - OHMTX的体内暴露量为MTX体内暴露量的2% - 40%。7 - OHMTX体内暴露量低或高的治疗疗程与该代谢产物不同的尿液回收率无关。MTX羟基化的差异无法得到证实。由于输注结束后不久7 - OHMTX的浓度就很高，应选择特定的MTX测定方法来控制治疗。
