Chan K K, Hong P S, Tutsch K, Trump D L
School of Pharmacy, University of Southern California, Los Angeles 90033.
Cancer Res. 1994 Dec 15;54(24):6421-9.
The pharmacokinetics of cyclophosphamide (CP) and several important metabolites was studied in detail in six patients receiving CP alone and with a radio- and chemosensitizing agent, SR-2508. CP at 1000 mg/m2 was either infused in 20 min alone or given 2 h before an infusion of SR-2508 at 5 g/m2 over 20 min, both separated by 3 weeks, to the same patients in a randomized fashion. Plasma and 24-h urinary levels of CP and four metabolites: [4-hydroxycyclophosphamide (4-OH CP), phosphoramide mustard (PM), chloroethyl oxazolidin-2-one, and alcophosphamide] were monitored by a gas chromatographic-mass spectrometric-stable isotope dilution assay. CP plasma levels were found to decline monoexponentially with the appearance of transient saturation kinetics in some and a mean t1/2 of 5.2 h for patients treated with CP alone. Plasma 4-OH CP levels showed a mean peak concentration of 2.4 microM and declined approximately in parallel to those of CP. The major circulating metabolite was found to be PM with a mean peak concentration of 40 microM and a terminal t1/2 of 15 h. The mean area under the plasma concentration curve (AUC) ratios between metabolites and CP were: 4-OH CP, 0.0158; PM, 0.4518; and chloroethyl oxazolidin-2-one, 0.179 with alcophosphamide at low levels. No appreciable amount of nornitrogen mustard was detected. Mean urinary excretion was: CP, 10.8; 4-OH, CP, 0.5; PM, 39.0; alcophosphamide, 0.4; and chloroethyl oxazolidin-2-one, 3.0, all expressed as a percentage of CP dose. No statistically significant difference was detected in all standard pharmacokinetic parameters determined for both CP and metabolites between patients with CP alone and with SR 2508. Plasma 4-(p-nitrobenzyl)pyridine activity was found to correlate the closest with PM profiles, with respect to both standard pharmacokinetic parameters and AUC values. When plasma PM AUC values were plotted against AUC values of circulating 4-(p-nitrobenzyl)pyridine activity, a correlation coefficient of 0.859 (P < 0.001) was obtained. Together with the significant cytotoxicity of PM these data support a significant contribution of circulating PM in the antitumor effect of PM.
在6例单独接受环磷酰胺（CP）治疗以及接受CP与放射和化学增敏剂SR - 2508联合治疗的患者中，对CP及其几种重要代谢产物的药代动力学进行了详细研究。以随机方式，给同一批患者在20分钟内单独输注1000mg/m²的CP，或者在输注5g/m²的SR - 2508前2小时输注CP，二者均在20分钟内输注完毕，两次给药间隔3周。通过气相色谱 - 质谱 - 稳定同位素稀释法监测血浆和24小时尿液中环磷酰胺及其4种代谢产物[4 - 羟基环磷酰胺（4 - OH CP）、磷酰胺氮芥（PM）、氯乙基恶唑烷 - 2 - 酮和醛磷酰胺]的水平。发现单独接受CP治疗的患者中，CP血浆水平呈单指数下降，部分患者出现短暂的饱和动力学，平均半衰期为5.2小时。血浆4 - OH CP水平的平均峰值浓度为2.4μM，其下降趋势与CP大致平行。发现主要的循环代谢产物是PM，平均峰值浓度为40μM，终末半衰期为15小时。代谢产物与CP之间血浆浓度曲线下平均面积（AUC）比值分别为：4 - OH CP为0.0158；PM为0.4518；氯乙基恶唑烷 - 2 - 酮为0.179，醛磷酰胺水平较低。未检测到可观量的去甲氮芥。平均尿排泄量分别为：CP为10.8%；4 - OH CP为0.5%；PM为39.0%；醛磷酰胺为0.4%；氯乙基恶唑烷 - 2 - 酮为3.0%，均以CP剂量的百分比表示。在单独接受CP治疗的患者和接受CP与SR - 2508联合治疗的患者中，所测定的CP及其代谢产物的所有标准药代动力学参数均未检测到统计学显著差异。就标准药代动力学参数和AUC值而言，发现血浆4 -（对硝基苄基）吡啶活性与PM曲线相关性最密切。当绘制血浆PM AUC值与循环4 -（对硝基苄基）吡啶活性的AUC值时，得到的相关系数为0.859（P < 0.001）。连同PM的显著细胞毒性，这些数据支持循环PM在PM抗肿瘤作用中起重要作用。
