聚维酮固体分散体递送紫杉醇的药代动力学、组织分布和抗肿瘤疗效。
Pharmacokinetics, tissue distribution and anti-tumour efficacy of paclitaxel delivered by polyvinylpyrrolidone solid dispersion.
机构信息
Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, China.
出版信息
J Pharm Pharmacol. 2012 Jun;64(6):775-82. doi: 10.1111/j.2042-7158.2012.01471.x. Epub 2012 Feb 27.
OBJECTIVES
Paclitaxel is a potent anti-cancer drug that has exhibited clinical activity against several tumours. Unfortunately, serious side effects are associated with Taxol, the commercial formulation of paclitaxel, which contains Cremophor EL (CrEL). Currently, the main focus of developing paclitaxel formulations is on improving efficacy and reducing toxicity. A novel, Cremophor-free, paclitaxel solid dispersion (PSD) was prepared in our laboratory previously. The primary aim of this study was to evaluate the pharmacokinetics, tissue distribution, acute toxicity and anti-tumour efficacy of the PSD compared with Taxol.
METHODS
SD rats were used to examine the pharmacokinetics and tissue distribution of PSD. The acute toxicity of PSD was evaluated in ICR mouse. The anti-tumor activity of PSD was assessed in an in vivo anti-tumor nude mice model inoculated with human SKOV-3 cancer cells.
KEY FINDINGS
The two formulations presented different pharmacokinetic behaviour. The plasma AUC of paclitaxel in the PSD was 5.84-fold lower than that of Taxol, and the mean residence time, total body clearance and apparent volume of distribution of paclitaxel in the PSD were increased by 1.73, 4.67 and 8.57 fold, respectively. However, the two formulations showed similar tissue distribution properties. CrEL, the vehicle in Taxol, decreased the clearance of paclitaxel from plasma. The LD50 (median lethal dose) was 34.8 mg/kg for Taxol, whereas no death was observed at 160 mg/kg for the PSD. The anti-tumour activity of PSD was similar to that of Taxol at a dose of 15 mg/kg. Most importantly, the improved tolerance of PSD enabled a higher administrable dose of paclitaxel, which resulted in improved efficacy compared with Taxol administered at its maximum tolerated dose.
CONCLUSIONS
These results suggest that the PSD, a CrEL-free formulation, is a promising approach to increase the safety and efficacy of paclitaxel.
目的
紫杉醇是一种有效的抗癌药物，对多种肿瘤具有临床活性。不幸的是，紫杉醇的商业制剂 Taxol 伴随着严重的副作用，其含有 Cremophor EL（CrEL）。目前，开发紫杉醇制剂的主要重点是提高疗效和降低毒性。我们实验室之前制备了一种新型的、不含 Cremophor 的紫杉醇固体分散体（PSD）。本研究的主要目的是评估 PSD 与 Taxol 相比的药代动力学、组织分布、急性毒性和抗肿瘤疗效。
方法
SD 大鼠用于研究 PSD 的药代动力学和组织分布。ICR 小鼠评估 PSD 的急性毒性。在接种人 SKOV-3 癌细胞的体内抗肿瘤裸鼠模型中评估 PSD 的抗肿瘤活性。
主要发现
两种制剂表现出不同的药代动力学行为。PSD 中紫杉醇的血浆 AUC 比 Taxol 低 5.84 倍，紫杉醇在 PSD 中的平均停留时间、总清除率和表观分布容积分别增加了 1.73、4.67 和 8.57 倍。然而，两种制剂显示出相似的组织分布特性。CrEL，Taxol 中的赋形剂，降低了紫杉醇从血浆中的清除率。Taxol 的 LD50（半数致死剂量）为 34.8mg/kg，而 PSD 为 160mg/kg 时没有死亡。PSD 在 15mg/kg 剂量时的抗肿瘤活性与 Taxol 相似。最重要的是，PSD 的耐受性改善使紫杉醇的可管理剂量更高，与 Taxol 以其最大耐受剂量给药相比，疗效得到改善。
结论
这些结果表明，不含 CrEL 的 PSD 是一种有前途的方法，可以提高紫杉醇的安全性和疗效。
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