Boddy A V, English M, Pearson A D, Idle J R, Skinner R
Department of Oncology, University of Newcastle upon Tyne, U.K.
Eur J Cancer. 1996 Jun;32A(7):1179-84. doi: 10.1016/0959-8049(96)00019-6.
This study investigated the relationship between both acute and chronic nephrotoxic effects of ifosfamide (IFO) and its metabolism. 15 paediatric patients (4 girls) were investigated. Each received 6-9 g/m2 IFO over 15 days, repeated every 3 weeks for up to 16 courses. The pharmacokinetics and metabolism of IFO were measured during its administration, either as a continuous 72 h infusion or as three bolus doses of 3 g/m2 on consecutive days. In 8 patients, the metabolism of IFO was investigated during one early course and one late course to determine the magnitude of any changes following repeated administration. Acute measures of renal toxicity were not correlated with any of the IFO pharmacokinetic or metabolic parameters in the same course, whether the drug was administered as a bolus or by continuous infusion. Chronic renal toxicity, determined 1 month (n = 13) or 6 months (n = 8) after treatment, did not correlate with any of the IFO pharmacokinetic or metabolic parameters in any individual course of treatment. The overall degree of nephrotoxicity, however, was correlated with the changes in metabolism between late and early courses (n = 8). There was a negative correlation between the change in area under the curve of the dechloroethylated metabolites of IFO and the overall nephrotoxicity at 1 month or 6 months after treatment (both r2 = 0.66, P = 0.014). The results imply that patients in whom metabolism via dechloroethylation decreases are at a greater risk of chronic nephrotoxicity. This is contrary to the hypothesis that the systemic production of chloroacetaldehyde is the mechanism by which IFO causes nephrotoxicity. The importance of acute and chronic changes in renal function for long-term outcome remains to be determined.
本研究调查了异环磷酰胺（IFO）的急性和慢性肾毒性作用与其代谢之间的关系。对15例儿科患者（4名女孩）进行了研究。每位患者在15天内接受6 - 9 g/m²的IFO，每3周重复一次，最多进行16个疗程。在IFO给药期间，通过持续72小时输注或连续3天每天给予3 g/m²的三次大剂量注射来测量其药代动力学和代谢情况。在8例患者中，在一个早期疗程和一个晚期疗程中研究了IFO的代谢情况，以确定重复给药后任何变化的程度。无论药物是以大剂量注射还是持续输注的方式给药，在同一疗程中，肾毒性的急性指标与任何IFO药代动力学或代谢参数均无相关性。在治疗后1个月（n = 13）或6个月（n = 8）测定的慢性肾毒性与任何单个治疗疗程中的IFO药代动力学或代谢参数均无相关性。然而，肾毒性的总体程度与晚期和早期疗程之间的代谢变化相关（n = 8）。IFO脱氯乙基代谢产物曲线下面积的变化与治疗后1个月或6个月时的总体肾毒性呈负相关（r²均 = 0.66，P = 0.014）。结果表明，通过脱氯乙基化代谢途径减少的患者发生慢性肾毒性的风险更高。这与氯乙醛的全身产生是IFO导致肾毒性的机制这一假设相反。肾功能急性和慢性变化对长期预后的重要性仍有待确定。
