Sparreboom A, van Tellingen O, Nooijen W J, Beijnen J H
Department of Clinical Chemistry, Antoni van Leeuwenhoek Huis, the Netherlands Cancer Institute, Amsterdam, The Netherlands.
Cancer Res. 1996 May 1;56(9):2112-5.
Studies in humans and mice have demonstrated a nonlinear pharmacokinetic behavior of paclitaxel. Because of its poor water solubility, the drug is formulated in a mixture of Cremophor EL and ethanol (1:1, v/v; Taxol). We hypothesized that the substantial amounts of concurrently administered Cremophor EL on the disposition of paclitaxel, female FVB mice received paclitazel by i.v. injection at does levels of 2, 10, and 20 mg/kg by appropriate (standard) dilution of the commercially available formulation of paclitaxel (Taxol) with saline. The drug was also given at 2 mg/kg with supplemental Cremophor EL-ethanol to achieve the same amount of vehicle as by standard administration of 10 mg/kg. Furthermore, paclitaxel formulations in Tween 80-ethanol (1:1, v/v) and dimethylacetamide were tested. Plasma samples were collected between 5 min and 48 h, and tissue specimens were sampled at 1, 4, and 8 h after drug administration. Paclitaxel and metabolites were quantified by high-performance liquid chromatography. Cremophor EL levels were determined by a novel high-performance liquid chromatography procedure. For comparative reasons, Cremophor EL was also assayed in plasma samples from three patients receiving a 3-h i.v. infusion of 175 mg/m2 of paclitaxel. A marked nonlinear pharmacokinetic behavior of paclitaxel was observed when the drug was formulated in Cremophor EL-ethanol. The clearance of 2.37 L/h/kg at 2 mg/kg was reduced to 0.33 and 0.15 L/h/kg at 10 and 20 mg/kg, respectively. When 2 mg/kg were given with an amount of Cremophor EL-ethanol matching that of the 10-mg/kg dose level, the clearance was 0.56 L/h/kg. If administered at 10 mg/kg in Tween 80-ethanol or at 2 and 10 mg/kg in dimethylacetamide, the clearances were 2.66, 2.57, and 2.62 L/h/kg, respectively. Despite the fact that much higher plasma levels of paclitaxel are reached when given in the Cremophor EL-ethanol formulation, the tissue levels were essentially similar with all tested drug preparations. The Cremophor EL levels in patients were in the same order of magnitude as those observed in mice after administration of 2 and 10 mg/kg. These data demonstrate that Cremophor EL has a profound effect on the pharmacokinetics of paclitaxel im mice. Because Cremophor EL also contributes substantially to the nonlinear pharmacokinetic behavior of paclitaxel observed in humans.
对人类和小鼠的研究已证明紫杉醇具有非线性药代动力学行为。由于其水溶性差，该药物被制成聚氧乙烯蓖麻油（Cremophor EL）和乙醇的混合物（1:1，v/v；泰素）。我们推测，同时给予的大量Cremophor EL会对紫杉醇的处置产生影响，因此，雌性FVB小鼠通过静脉注射给予不同剂量的紫杉醇，剂量水平分别为2、10和20mg/kg，通过用生理盐水对市售紫杉醇制剂（泰素）进行适当（标准）稀释来实现。还以2mg/kg的剂量给予补充的Cremophor EL - 乙醇，以使赋形剂的量与10mg/kg标准给药时相同。此外，还测试了吐温80 - 乙醇（1:1，v/v）和二甲基乙酰胺中的紫杉醇制剂。在5分钟至48小时之间采集血浆样本，并在给药后1、4和8小时采集组织标本。通过高效液相色谱法定量测定紫杉醇及其代谢物。通过一种新型高效液相色谱法测定Cremophor EL水平。出于比较目的，还对三名接受3小时静脉输注175mg/m²紫杉醇的患者的血浆样本进行了Cremophor EL测定。当药物制成Cremophor EL - 乙醇制剂时，观察到紫杉醇具有明显的非线性药代动力学行为。2mg/kg时的清除率为2.37L/h/kg，在10mg/kg和20mg/kg时分别降至0.33和0.15L/h/kg。当以2mg/kg给予与10mg/kg剂量水平相同量的Cremophor EL - 乙醇时，清除率为0.56L/h/kg。如果以10mg/kg在吐温80 - 乙醇中给药或以2mg/kg和10mg/kg在二甲基乙酰胺中给药，清除率分别为2.66、2.57和2.62L/h/kg。尽管当以Cremophor EL - 乙醇制剂给药时达到的紫杉醇血浆水平要高得多，但所有测试药物制剂的组织水平基本相似。患者体内的Cremophor EL水平与给予2mg/kg和10mg/kg后在小鼠中观察到的水平处于同一数量级。这些数据表明，Cremophor EL对小鼠体内紫杉醇的药代动力学有深远影响。因为Cremophor EL也在很大程度上导致了在人类中观察到的紫杉醇非线性药代动力学行为。
