Boddy A V, Furtun Y, Sardas S, Sardas O, Idle J R
Department of Pharmacological Sciences, Medical School, University of Newcastle upon Tyne, England.
J Natl Cancer Inst. 1992 Nov 18;84(22):1744-8. doi: 10.1093/jnci/84.22.1744.
Carboxyphosphamide is an inactive metabolite of cyclophosphamide, which is a widely used antineoplastic drug. Deficiencies in the production of this metabolite have been reported. Such deficiencies would have important consequences for therapeutic and toxic effects of oxazaphosphorines like cyclophosphamide.
This study further investigates the variability in cyclophosphamide metabolism and carboxyphosphamide recovery in urine.
The 24-hour urinary metabolic profile of cyclophosphamide was investigated in 17 Turkish patients receiving doses of 100-1080 mg orally or by short intravenous infusion. Urine samples were assayed quantitatively for cyclophosphamide and its principal metabolites (phosphoramide mustard, 4-ketocyclophosphamide, carboxyphosphamide, and dechloroethylcyclophosphamide) with combined thin-layer chromatography-photography-densitometry. The amount of each metabolite excreted in 24 hours was expressed as a percentage of the dose.
Recovery of drug and metabolites varied greatly among individuals (range, 0.01%-13.56% of dose). In particular, the amount of carboxyphosphamide varied over a thousandfold range and was undetectable in urine from four patients. The patients were classified by phenotype as demonstrating low or high carboxylation. Those with low carboxylation excreted less than 0.2% of the cyclophosphamide dose as carboxyphosphamide, while those with high carboxylation excreted 0.8%-13.6% (median, 1.81%). No association was observed between carboxylation phenotype and patient age, sex, disease, or concomitant therapy, although the three lifetime nonsmokers all showed poor carboxylation. No correlation was observed between the percent of dose excreted as any of the other metabolites and that excreted as carboxyphosphamide. There was a statistically significant inverse correlation between the combined recovery of carboxyphosphamide and phosphoramide mustard and the dose of prednisolone administered.
These data confirm an earlier observation of a phenotypic deficiency of carboxyphosphamide excretion in British patients treated with cyclophosphamide. This deficiency may arise from a polymorphism in the enzyme aldehyde dehydrogenase. Carboxylation phenotype may have important implications for both the therapeutic effect and toxicity of cyclophosphamide.
羧磷酰胺是环磷酰胺的一种无活性代谢产物，环磷酰胺是一种广泛使用的抗肿瘤药物。已有报道称该代谢产物的生成存在缺陷。这种缺陷会对像环磷酰胺这样的氮杂磷类药物的治疗效果和毒性产生重要影响。
本研究进一步探究环磷酰胺代谢及尿液中羧磷酰胺回收的变异性。
对17名接受口服或短时间静脉输注100 - 1080mg剂量环磷酰胺的土耳其患者，研究其24小时尿液代谢情况。采用薄层色谱 - 摄影 - 光密度法联合对尿液样本中的环磷酰胺及其主要代谢产物（磷酰胺氮芥、4 - 酮环磷酰胺、羧磷酰胺和去氯乙基环磷酰胺）进行定量分析。将24小时内排出的每种代谢产物的量表示为给药剂量的百分比。
药物和代谢产物的回收在个体间差异很大（范围为给药剂量的0.01% - 13.56%）。特别是，羧磷酰胺的量变化范围超过千倍，且在4名患者的尿液中未检测到。患者按表型分为低羧化或高羧化。低羧化患者排出的羧磷酰胺占环磷酰胺剂量的比例小于0.2%，而高羧化患者排出的比例为0.8% - 13.6%（中位数为1.81%）。尽管3名终生不吸烟者均表现出低羧化，但未观察到羧化表型与患者年龄、性别、疾病或伴随治疗之间存在关联。作为其他任何一种代谢产物排出的剂量百分比与作为羧磷酰胺排出的剂量百分比之间未观察到相关性。羧磷酰胺和磷酰胺氮芥的联合回收与泼尼松龙给药剂量之间存在统计学上的显著负相关。
这些数据证实了先前在接受环磷酰胺治疗的英国患者中观察到的羧磷酰胺排泄表型缺陷。这种缺陷可能源于醛脱氢酶的多态性。羧化表型可能对环磷酰胺的治疗效果和毒性都具有重要意义。
