ten Tije Albert J, Verweij Jaap, Loos Walter J, Sparreboom Alex
Department of Medical Oncology, Erasmus MC - Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
Clin Pharmacokinet. 2003;42(7):665-85. doi: 10.2165/00003088-200342070-00005.
The non-ionic surfactants Cremophor EL (CrEL; polyoxyethyleneglycerol triricinoleate 35) and polysorbate 80 (Tween) 80; polyoxyethylene-sorbitan-20-monooleate) are widely used as drug formulation vehicles, including for the taxane anticancer agents paclitaxel and docetaxel. A wealth of recent experimental data has indicated that both solubilisers are biologically and pharmacologically active compounds, and their use as drug formulation vehicles has been implicated in clinically important adverse effects, including acute hypersensitivity reactions and peripheral neuropathy.CrEL and Tween 80 have also been demonstrated to influence the disposition of solubilised drugs that are administered intravenously. The overall resulting effect is a highly increased systemic drug exposure and a simultaneously decreased clearance, leading to alteration in the pharmacodynamic characteristics of the solubilised drug. Kinetic experiments revealed that this effect is primarily caused by reduced cellular uptake of the drug from large spherical micellar-like structures with a highly hydrophobic interior, which act as the principal carrier of circulating drug. Within the central blood compartment, this results in a profound alteration of drug accumulation in erythrocytes, thereby reducing the free drug fraction available for cellular partitioning and influencing drug distribution as well as elimination routes. The existence of CrEL and Tween 80 in blood as large polar micelles has also raised additional complexities in the case of combination chemotherapy regimens with taxanes, such that the disposition of several coadministered drugs, including anthracyclines and epipodophyllotoxins, is significantly altered. In contrast to the enhancing effects of Tween 80, addition of CrEL to the formulation of oral drug preparations seems to result in significantly diminished drug uptake and reduced circulating concentrations. The drawbacks presented by the presence of CrEL or Tween 80 in drug formulations have instigated extensive research to develop alternative delivery forms. Currently, several strategies are in progress to develop Tween 80- and CrEL-free formulations of docetaxel and paclitaxel, which are based on pharmaceutical (e.g. albumin nanoparticles, emulsions and liposomes), chemical (e.g. polyglutamates, analogues and prodrugs), or biological (e.g. oral drug administration) strategies. These continued investigations should eventually lead to more rational and selective chemotherapeutic treatment.
非离子表面活性剂聚氧乙烯蓖麻油（CrEL；聚氧乙烯甘油三蓖麻酸酯35）和聚山梨酯80（吐温80；聚氧乙烯脱水山梨醇单油酸酯20）被广泛用作药物制剂载体，包括用于紫杉烷类抗癌药物紫杉醇和多西他赛。最近大量的实验数据表明，这两种增溶剂都是具有生物活性和药理活性的化合物，它们作为药物制剂载体的使用与临床上重要的不良反应有关，包括急性过敏反应和周围神经病变。CrEL和吐温80也已被证明会影响静脉给药的增溶药物的处置。总体结果是全身药物暴露显著增加，同时清除率降低，导致增溶药物的药效学特性发生改变。动力学实验表明，这种效应主要是由于药物从具有高度疏水内部的大球形胶束样结构的细胞摄取减少所致，这种结构是循环药物的主要载体。在中央血室中，这会导致红细胞中药物蓄积的深刻改变，从而减少可用于细胞分配的游离药物分数，并影响药物分布以及消除途径。在含紫杉烷类的联合化疗方案中，血液中以大极性胶束形式存在的CrEL和吐温80也带来了额外的复杂性，使得几种共同给药的药物，包括蒽环类药物和鬼臼毒素类药物的处置发生显著改变。与吐温80的增强作用相反，在口服药物制剂中添加CrEL似乎会导致药物摄取显著减少和循环浓度降低。药物制剂中CrEL或吐温80的存在所带来的缺点促使人们进行广泛研究以开发替代给药形式。目前，正在进行几种策略来开发不含吐温80和CrEL的多西他赛和紫杉醇制剂，这些策略基于药学（如白蛋白纳米颗粒、乳剂和脂质体）、化学（如聚谷氨酸盐、类似物和前药）或生物学（如口服给药）策略。这些持续的研究最终应会带来更合理、更具选择性的化疗治疗。
