Ifosfamide nephrotoxicity: Limited Influence of metabolism and mode of administration during repeated therapy in paediatrics
Ifosfamide nephrotoxicity: Limited Influence of metabolism and mode of administration during repeated therapy in paediatrics
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DOI：
10.1016/0959-8049(96)00019-6
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发表时间：
1996-06-01
影响因子：
8.4
通讯作者：
Skinner, R
中科院分区：
文献类型：
--
作者：
Boddy, AV;English, M;Skinner, R
本研究探讨了异环磷酰胺（IFO）的急性和慢性肾毒性作用与其代谢之间的关系。研究了15名儿科患者（4名女孩）。每个人在15天内接受6-9 g/m2的IFO，每3周重复一次，最多16个疗程。IFO的药代动力学和代谢在其给药期间进行了测量，无论是连续72小时输注还是连续几天3 g/m2的三次推注剂量。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，以确定重复给药后任何变化的幅度。急性肾毒性指标与同一过程中IFO的任何药代动力学或代谢参数无关，无论药物是作为推注还是通过连续输注给药。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个体疗程中的任何IFO药代动力学或代谢参数均不相关。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去氯乙基代谢物曲线下面积的变化与治疗后1个月或6个月的总体肾毒性呈负相关（均r（2）= 0.66，P = 0.014）。结果表明，通过脱氯乙基化代谢降低的患者发生慢性肾毒性的风险更大。这与IFO引起肾毒性的机制是氯乙醛的全身产生的假设相反。急性和慢性肾功能变化对长期预后的重要性仍有待确定。版权所有（C）1996 Elsevier Science Ltd
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/m(2) 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/m(2) 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 r(2) = 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. Copyright (C) 1996 Elsevier Science Ltd