van Zuylen L, Karlsson M O, Verweij J, Brouwer E, de Bruijn P, Nooter K, Stoter G, Sparreboom A
Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, 3075 EA Rotterdam, The Netherlands.
Cancer Chemother Pharmacol. 2001 Apr;47(4):309-18. doi: 10.1007/s002800000215.
Nonlinear disposition of paclitaxel (Taxol) in cancer patients has been described in several studies, but the underlying mechanism is still a matter of speculation. Previously, we have shown in vitro that the paclitaxel formulation vehicle, Cremophor EL (CrEL), alters the blood distribution of paclitaxel as a result of entrapment of the compound in circulating CrEL micelles, thereby reducing the free drug fraction available for cellular partitioning. Based on these findings, we prospectively re-evaluated the linearity of paclitaxel disposition in patients using whole blood and plasma analysis, and sought to define a new pharmacokinetic model to describe the data. Seven patients with solid tumors were treated with paclitaxel infused over 3 h, each at consecutive 3-weekly dose levels of 225, 175 and 135 mg/m2 (CrEL dose level, 18.8, 14.6, and 11.3 ml/m2, respectively). Patient samples were collected up to 24 h after the start of infusion, and analyzed by high-performance liquid chromatography. Paclitaxel peak levels and areas under the curve in whole blood increased linearly with dose, whereas plasma levels showed substantial deviation from linearity. This was shown to be caused by a CrEL concentration-dependent decrease in paclitaxel uptake in blood cells, as reflected by the blood:plasma concentration ratios which altered significantly from 0.83 +/- 0.11 (at 135 mg/m2) to 0.68 +/- 0.07 (at 225 mg/m2). It is concluded that the nonlinear disposition of paclitaxel is related to paclitaxel dose-related levels of the formulation vehicle CrEL, leading to a disproportionate drug accumulation in the plasma fraction. The pharmacokinetic model developed accurately described the data, and will help guide future development and refinement of clinical protocols, especially in defining the exposure measure best linked to paclitaxel effects and toxicities.
多项研究已描述了癌症患者中紫杉醇（泰素）的非线性处置，但潜在机制仍存在推测。此前，我们在体外已表明，紫杉醇制剂载体聚氧乙烯蓖麻油（CrEL）会改变紫杉醇的血液分布，这是由于该化合物被包裹在循环的CrEL胶束中，从而降低了可用于细胞分配的游离药物分数。基于这些发现，我们前瞻性地使用全血和血浆分析重新评估了患者中紫杉醇处置的线性，并试图定义一个新的药代动力学模型来描述这些数据。七名实体瘤患者接受了3小时输注的紫杉醇治疗，每次连续3周的剂量水平分别为225、175和135mg/m²（CrEL剂量水平分别为18.8、14.6和11.3ml/m²）。在输注开始后长达24小时收集患者样本，并通过高效液相色谱法进行分析。全血中紫杉醇的峰值水平和曲线下面积随剂量呈线性增加，而血浆水平则显示出与线性有显著偏差。这被证明是由于血细胞中紫杉醇摄取的CrEL浓度依赖性降低所致，这反映在血药浓度与血浆浓度之比上，该比值从0.83±0.11（135mg/m²时）显著变化至0.68±0.07（225mg/m²时）。结论是，紫杉醇的非线性处置与制剂载体CrEL的紫杉醇剂量相关水平有关，导致药物在血浆部分不成比例地积累。所建立的药代动力学模型准确地描述了数据，并将有助于指导未来临床方案的开发和完善，特别是在确定与紫杉醇效应和毒性最相关的暴露测量方面。
