Föger Florian, Malaivijitnond Suchinda, Wannaprasert Thanakul, Huck Christian, Bernkop-Schnürch Andreas, Werle Martin
Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens University Innsbruck, Innsbruck, Austria.
J Drug Target. 2008 Feb;16(2):149-55. doi: 10.1080/10611860701850130.
The anticancer agent paclitaxel is currently commercially available only as an infusion due to its low oral bioavailability. An oral formulation would be highly beneficial for patients. Besides the low solubility, the main reason for the limited oral bioavailability of paclitaxel is that it is a substrate of the efflux pump P-glycoprotein (P-gp). Recently, it has been demonstrated that P-gp can be inhibited by thiolated polymers. In this study, an oral paclitaxel formulation based on thiolated polycarbophil was evaluated in vivo in wild-type rats and in mammary cancer-induced rats. The paclitaxel plasma level after a single administration of paclitaxel was observed for 12 h in healthy rats. Moreover, cancer-induced rats were treated weekly for 5 weeks with the novel formulation. It was demonstrated that (1) co-administration of thiolated polycarbophil significantly improved paclitaxel plasma levels, (2) a more constant pharmacokinetic profile could be achieved and (3) the tumor growth was reduced. These effects can most likely be attributed to P-gp inhibition. According to the achieved results, thiolated polymers are believed to be interesting tools for the delivery of P-gp substrates such as paclitaxel.
抗癌药物紫杉醇由于口服生物利用度低，目前仅以静脉输注形式上市。口服制剂对患者将非常有益。除了溶解度低之外，紫杉醇口服生物利用度有限的主要原因是它是外排泵P-糖蛋白（P-gp）的底物。最近，已证明硫醇化聚合物可抑制P-gp。在本研究中，基于硫醇化聚卡波非的口服紫杉醇制剂在野生型大鼠和乳腺癌诱导大鼠体内进行了评估。在健康大鼠中观察了单次给予紫杉醇后12小时内的紫杉醇血浆水平。此外，用新制剂对癌症诱导大鼠每周治疗5周。结果表明：（1）硫醇化聚卡波非的共同给药显著提高了紫杉醇血浆水平；（2）可以实现更稳定的药代动力学特征；（3）肿瘤生长受到抑制。这些作用很可能归因于P-gp抑制。根据所取得的结果，硫醇化聚合物被认为是递送P-gp底物如紫杉醇的有趣工具。
