Alberts D S, Peng Y M, Leigh S, Davis T P, Woodward D L
Cancer Res. 1985 Apr;45(4):1879-84.
We have used a highly sensitive high-performance liquid chromatographic assay to evaluate the pharmacokinetics and tissue disposition of mitoxantrone, an investigational anthracene derivative which has shown significant activity during Phase II clinical trials in the treatment of metastatic breast cancer, unfavorable histology non-Hodgkin's lymphoma, and acute leukemia. Mitoxantrone (12 mg/sq m over 30 to 35 min in 250 ml of dextrose 5% in water) and 14C-labeled mitoxantrone (specific activity, 8.85 muCi/mg) were administered to eight patients who had advanced soft tissue cancers. The plasma disappearance of mitoxantrone concentrations measured by high-performance liquid chromatography was best described by a three-compartment model with a mean t alpha of 0.1 h, a t beta of 1.1 h, and a t gamma of 42.6 h. The mean apparent Vc was 12.2 liters/sq m, while the mean Vd was 1875 liters/sq m. The mean plasma clearance was 0.57 liters/min/sq m, and the mean renal clearance was 45 ml/min/sq m. Only 6.5% of the total mitoxantrone dose was excreted in the urine as unchanged drug over 5 days. The mean recovery of 14C-labeled material in feces over 5 days was 18.3% of the administered dose. Thirty-five days after mitoxantrone administration to a patient who died of progressive kidney cancer, approximately 15% of the 14C dose could be accounted for in seven major organs. We conclude that mitoxantrone appears to distribute into a deep tissue compartment from which it is slowly released. These data provide a pharmacological rationale for use of mitoxantrone on an intermittent dosing schedule.
我们采用了一种高灵敏度的高效液相色谱分析法，来评估米托蒽醌的药代动力学及组织分布情况。米托蒽醌是一种正在研究的蒽衍生物，在转移性乳腺癌、不良组织学类型的非霍奇金淋巴瘤及急性白血病的II期临床试验中已显示出显著活性。对8例患有晚期软组织癌的患者给予米托蒽醌（12mg/平方米，于250ml 5%葡萄糖水溶液中在30至35分钟内输注）及14C标记的米托蒽醌（比活度为8.85μCi/mg）。通过高效液相色谱法测定的米托蒽醌浓度的血浆消除情况，可用三室模型最佳描述，平均α相半衰期为0.1小时，β相半衰期为1.1小时，γ相半衰期为42.6小时。平均表观分布容积为12.2升/平方米，而平均分布容积为1875升/平方米。平均血浆清除率为0.57升/分钟/平方米，平均肾清除率为45毫升/分钟/平方米。在5天内，仅6.5%的米托蒽醌总剂量以原形药物形式经尿液排泄。5天内粪便中14C标记物的平均回收量为给药剂量的18.3%。在一名死于进行性肾癌的患者接受米托蒽醌给药35天后，七个主要器官中约可找到14C剂量的15%。我们得出结论，米托蒽醌似乎分布至一个深部组织隔室，且从该隔室中缓慢释放。这些数据为米托蒽醌采用间歇给药方案提供了药理学依据。
