Sparreboom A, van Tellingen O, Nooijen W J, Beijnen J H
Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, The Netherlands.
Anticancer Drugs. 1998 Jan;9(1):1-17. doi: 10.1097/00001813-199801000-00001.
The taxanes paclitaxel and docetaxel represent a novel class of antineoplastic agents. A major problem of both drugs is their low aqueous solubility and the design of suitable formulations has been a difficult step in the process of therapeutic development. The formulations currently used are mixtures of Cremophor EL:ethanol for paclitaxel (Taxol) and Tween 80:ethanol for docetaxel (Taxotere), but many new approaches have been tested or are under investigation. Paclitaxel and docetaxel have a similar mechanism of action, which is based on promotion of tubulin assembly and inhibition of microtubule disassembly. Pharmacokinetic studies revealed a marked non-linearity of paclitaxel in mice, which appeared to result exclusively from Cremophor EL, the major component present in the pharmaceutical formulation. An almost linear pharmacokinetic behavior was observed in the case of docetaxel. The reported plasma protein binding of both compounds ranged from 76 to 97% in different animal species. Paclitaxel and docetaxel widely distribute into most tissues of mice and rats, including tumor tissue, but only low concentrations were detected in the central nervous system. Despite the great similarity in the chemical structures of paclitaxel and docetaxel, their metabolic profile is very distinct. Furthermore, whereas paclitaxel metabolism is largely species dependent, docetaxel metabolism is similar across species in both isolated hepatic microsomal fractions and in vivo models. For both taxanes, hepatobiliary excretion is the major pathway of elimination and a major fraction of the dose is excreted in feces as parent drug or hydroxylated metabolites.
紫杉烷类的紫杉醇和多西他赛是一类新型抗肿瘤药物。这两种药物的一个主要问题是它们的水溶性低，在治疗开发过程中设计合适的制剂一直是一个难题。目前使用的制剂是用于紫杉醇（泰素）的聚氧乙烯蓖麻油（Cremophor EL）：乙醇混合物和用于多西他赛（泰索帝）的吐温80：乙醇混合物，但已经测试了许多新方法或正在进行研究。紫杉醇和多西他赛具有相似的作用机制，即促进微管蛋白组装并抑制微管解聚。药代动力学研究表明，紫杉醇在小鼠体内有明显的非线性，这似乎完全是由药物制剂中的主要成分聚氧乙烯蓖麻油引起的。在多西他赛的情况下观察到几乎呈线性的药代动力学行为。在不同动物物种中，这两种化合物的血浆蛋白结合率报道为76%至97%。紫杉醇和多西他赛广泛分布于小鼠和大鼠的大多数组织中，包括肿瘤组织，但在中枢神经系统中仅检测到低浓度。尽管紫杉醇和多西他赛的化学结构非常相似，但它们的代谢谱却截然不同。此外，紫杉醇的代谢在很大程度上取决于物种，而多西他赛在分离的肝微粒体部分和体内模型中的代谢在不同物种间相似。对于这两种紫杉烷类药物，肝胆排泄是主要的消除途径，大部分剂量以原形药物或羟基化代谢产物的形式随粪便排出。
