Jarman M, Milsted R A, Smyth J F, Kinas R W, Pankiewicz K, Stec W J
Cancer Res. 1979 Jul;39(7 Pt 1):2762-7.
The comparative metabolism of the enantiomers of cyclo phosphamide and of the racemate has been studied in humans. Four patients were each given, sequentially, the racemate, the (+)-enantiomer, and its (-)-antipode. The plasma levels of parent drug and the urinary output (24 hr) of unchanged drug and of two enzymatically produced metabolites, 4-ketocyclophosphamide and carboxyphosphamide, were determined using mass spectrometry-stable isotope dilution. There was no significant difference between the three forms of cyclophosphamide with respect to plasma half-life (beta phase) or in the urinary outputs of the drug or of carboxyphosphamide. The output of 4-ketocyclophosphamide after administration of (+)-cyclophosphamide was significantly greater than that produced from the racemate. Cyclophosphamide recovered from the urine of patients given the racemate was either racemic or only slightly enriched in the (-)-enantiomer. The two enantiomers were almost equally bound to plasma protein. Based on these metabolic studies alone, there is little reason to predict that the enantiomers will differ from each other or from the racemate in their therapeutic effects in humans, but there are other factors, e.g., stereoselective uptake of the intermediary 4-hydroxylated metabolites by neoplastic cells, which could elicit such differences.
环磷酰胺对映体及消旋体在人体内的比较代谢情况已得到研究。4名患者分别依次接受消旋体、（+）-对映体及其（-）-对映体。采用质谱-稳定同位素稀释法测定母体药物的血浆水平以及24小时内未变化药物和两种酶促产生的代谢物（4-酮环磷酰胺和羧基磷酰胺）的尿量。三种形式的环磷酰胺在血浆半衰期（β期）或药物及羧基磷酰胺的尿量方面无显著差异。给予（+）-环磷酰胺后4-酮环磷酰胺的产出量显著高于消旋体产生的量。从接受消旋体治疗的患者尿液中回收的环磷酰胺要么是外消旋的，要么仅在（-）-对映体中略有富集。两种对映体与血浆蛋白的结合几乎相等。仅基于这些代谢研究，几乎没有理由预测对映体在人体治疗效果上会彼此不同或与消旋体不同，但存在其他因素，例如肿瘤细胞对中间4-羟基化代谢物的立体选择性摄取，这可能会引发此类差异。
