Hartley J M, Nicholson P W, Allen R, Lamond P, Harland S J, Souhami R L
Department of Oncology, University College London Medical School, UK.
Cancer Chemother Pharmacol. 1993;31(4):328-32. doi: 10.1007/BF00685680.
We studied the pharmacokinetics of 10-ethyl-10-deaza-aminopterin (10-EdAM), edatrexate and its 7-hydroxy metabolite during a phase II trial of treatment in advanced non-small-cell lung cancer. A dose of 80 mg/m2 was given weekly, with dose reduction being undertaken for mucositis or haematological toxicity. A triphasic pattern of plasma elimination was seen, the mean half-lives being 0.10 +/- 0.07, 0.8 +/- 0.3 and 7 +/- 7 h, respectively. The mean plasma clearance was 25 +/- 14 l/h, with 18% +/- 11% of the dose appearing unchanged in the urine. The serum concentration at 1 h accurately predicted the area under the curve (AUC) with r2 = 0.976. There was considerable variation of the clearance both within and between patients but there was no evidence of a dependence on time or dose. The 1-h concentration of the drug was shown to be related to the incidence of toxicity requiring dose reduction. The change in WBC due to the initial dose was shown to be related to both the AUC of the drug and that of its 7-OH metabolite.
在一项针对晚期非小细胞肺癌的II期治疗试验中，我们研究了10-乙基-10-脱氮氨基蝶呤（10-EdAM）、依达曲沙及其7-羟基代谢产物的药代动力学。每周给予80 mg/m²的剂量，若出现粘膜炎或血液学毒性则进行剂量减少。观察到血浆消除呈三相模式，平均半衰期分别为0.10±0.07、0.8±0.3和7±7小时。平均血浆清除率为25±14 l/h，18%±11%的剂量以原形出现在尿液中。1小时时的血清浓度能准确预测曲线下面积（AUC），r² = 0.976。患者体内和患者之间的清除率存在相当大的差异，但没有证据表明其与时间或剂量有关。已表明药物的1小时浓度与需要减少剂量的毒性发生率有关。因初始剂量导致的白细胞变化与药物及其7-OH代谢产物的AUC均有关。
