Silies H, Blaschke G, Hohenlöchter B, Rossi R, Jürgens H, Boos J
Department of Pediatric Hematology and Oncology, University of Münster, Germany.
Int J Clin Pharmacol Ther. 1998 May;36(5):246-52.
Ifosfamide (IFO) requires metabolic activation by hydroxylation of the ring system to exert cytotoxic activity. A second metabolic pathway produces the cytostatically inactive metabolites 2-dechloroethyl-ifosfamide (2-D-IFO) and 3-dechloroethyl-ifosfamide (3-D-IFO) under release of chloroacetaldehyde. This side-chain metabolism has been suggested to be involved in CNS- and renal toxicity. The total urinary excretion of ifosfamide and its metabolites was investigated during 23 cycles in 22 children at doses ranging from 400 mg/m2 to 3 g/m2. The kinetics of the excretion were compared following short-term and continuous ifosfamide infusion at a dosage of 3 g/m2. IFO and side-chain metabolites were analyzed by gas chromatography, the active metabolites by indirect determination of acrolein (ACR) and IFO mustard (IFO-M) with the NBP test. 59+/-15% of the applied dose could be recovered in the urine, 23+/-9% as unmetabolized IFO. The main metabolite was 3-D-IFO (14+/-4%) followed by isophosphoramide mustard (IFO-M) (13+/-4%) and 2-D-IFO (8+/-3%). Neither the total amount recovered nor the excretion kinetics of ifosfamide and side-chain metabolites showed obvious schedule dependency. The excretion kinetics of side-chain metabolites as well as unmetabolized IFO were nearly superimposable on short-term and continuous infusion. Even after 1-hour infusion there was a lag of 3 - 6 hours until dechloroethylation became relevant. Therefore, differences in toxicity and efficacy cannot be explained by an influence of the application time on the metabolic profile of ifosfamide.
异环磷酰胺（IFO）需要通过环系统的羟基化进行代谢激活才能发挥细胞毒性活性。第二条代谢途径会产生细胞生长抑制活性不高的代谢产物2-去氯乙基-异环磷酰胺（2-D-IFO）和3-去氯乙基-异环磷酰胺（3-D-IFO），同时释放出氯乙醛。有人认为这种侧链代谢与中枢神经系统和肾脏毒性有关。在22名儿童的23个疗程中，研究了剂量范围为400mg/m²至3g/m²时异环磷酰胺及其代谢产物的总尿排泄情况。比较了以3g/m²的剂量短期和持续输注异环磷酰胺后排泄的动力学情况。通过气相色谱分析异环磷酰胺和侧链代谢产物，通过NBP试验间接测定丙烯醛（ACR）和异环磷酰胺氮芥（IFO-M）来分析活性代谢产物。所给剂量的59±15%可在尿液中回收，其中23±9%为未代谢的异环磷酰胺。主要代谢产物是3-D-IFO（14±4%），其次是异磷酰胺氮芥（IFO-M）（13±4%）和2-D-IFO（8±3%）。回收的总量以及异环磷酰胺和侧链代谢产物的排泄动力学均未显示出明显的给药方案依赖性。侧链代谢产物以及未代谢的异环磷酰胺的排泄动力学在短期和持续输注时几乎是重叠的。即使输注1小时后，直到去氯乙基化变得明显也会有3至6小时的延迟。因此，毒性和疗效的差异不能用给药时间对异环磷酰胺代谢谱的影响来解释。
