Kurowski V, Wagner T
Clinic for Internal Medicine, Medical University, Lübeck, Germany.
Cancer Chemother Pharmacol. 1997;39(5):431-9. doi: 10.1007/s002800050594.
The oxazaphosphorine antineoplastic ifosfamide (IF) is metabolized by two different initial pathways: ring oxidation ("activation"), forming 4-OH-IF ("activated IF"), and side-chain oxidation with liberation of chloroacetaldehyde (CAA), forming the inactive metabolites 3-dechloroethylifosfamide or 2-dechloroethylifosfamide (3-DCE-IF, 2-DCE-IF). 4-OH-IF and 4-OH-IF-derived acrolein are thought to be responsible for IF-induced urotoxicity (hemorrhagic cystitis), whereas CAA may be involved in IF-associated nephrotoxicity (renal tubular damage). The thiol compound 2-mercaptoethane sulfonate sodium (mesna) has proved to inactivate sufficiently the urotoxic metabolites of oxazaphosphorine cytostatics and is therefore routinely given to patients receiving IF chemotherapy. The cumulative urinary excretion of IF, 4-OH-IF, 3-DCE-IF, 2-DCE-IF, mesna, and its disulfide dimesna was studied in 11 patients with bronchogenic carcinoma receiving IF on a 5-day divided-dose schedule (1.5 g/m2 daily) with concomitant application of mesna (0.3 g/m2 at 0,4, and 8 h after IF infusion). On day 1 the mean cumulative 24-h urinary recoveries (percentage of the IF dose) recorded for IF, 4-OH-IF, 3-DCE-IF, and 2-DCE-IF were 13.9%, 0.52%, 4.8%, and 1.5%, respectively. On day 5 the corresponding values were 12.2%, 0.74%, 9.9%, and 3.6%, respectively. This time-dependent increase in urinary excretion of IF metabolites, which is caused by rapid autoinduction of hepatic oxidative metabolism, may result in a higher probability for the development of urotoxic and nephrotoxic side effects during prolonged IF application. The mean 24-h urinary recoveries (percentage of the daily mesna dose) recorded for mesna/dimesna on day 1 (day 5) were 23.8%/45.2% (21.2%/39.8%), respectively. The mean molar excess of urinary reduced ("free") mesna over 4-OH-IF ranged from 11 to 72 on day 1 and from 6 to 40 on day 5. This indicates that although urinary excretion of 4-OH-IF rises with repeated IF application, mesna in standard doses should sufficiently inactivate the urotoxic IF metabolites.
氮杂磷三环抗肿瘤药异环磷酰胺（IF）通过两种不同的初始途径进行代谢：环氧化（“活化”），形成4-羟基异环磷酰胺（“活化异环磷酰胺”），以及侧链氧化并释放氯乙醛（CAA），形成无活性代谢物3-去氯乙基异环磷酰胺或2-去氯乙基异环磷酰胺（3-DCE-IF，2-DCE-IF）。4-羟基异环磷酰胺及其衍生的丙烯醛被认为是IF诱导的泌尿毒性（出血性膀胱炎）的原因，而CAA可能与IF相关的肾毒性（肾小管损伤）有关。硫醇化合物2-巯基乙烷磺酸钠（美司钠）已被证明能充分灭活氮杂磷三环细胞抑制剂的泌尿毒性代谢物，因此在接受IF化疗的患者中常规使用。在11例支气管癌患者中，研究了IF、4-羟基异环磷酰胺、3-DCE-IF、2-DCE-IF、美司钠及其二硫化物二聚美司钠的累积尿排泄情况，这些患者接受IF的5天分次给药方案（每日1.5 g/m²），并同时应用美司钠（IF输注后0、4和8小时各0.3 g/m²）。第1天，IF、4-羟基异环磷酰胺、3-DCE-IF和2-DCE-IF的平均24小时累积尿回收率（IF剂量的百分比）分别为13.9%、0.52%、4.8%和1.5%。第5天，相应的值分别为12.2%、0.74%、9.9%和3.6%。IF代谢物尿排泄的这种时间依赖性增加是由肝脏氧化代谢的快速自身诱导引起的，这可能导致在长期应用IF期间发生泌尿毒性和肾毒性副作用的可能性更高。第1天（第5天）美司钠/二聚美司钠的平均24小时尿回收率（每日美司钠剂量的百分比）分别为23.8%/45.2%（21.2%/39.8%）。第1天尿中还原型（“游离”）美司钠相对于4-羟基异环磷酰胺的平均摩尔过量范围为11至72，第5天为6至40。这表明，尽管随着IF的重复应用，4-羟基异环磷酰胺的尿排泄量增加，但标准剂量的美司钠应能充分灭活IF的泌尿毒性代谢物。
