Bardelmeijer Heleen A, Ouwehand Mariët, Malingré Mirte M, Schellens Jan H M, Beijnen Jos H, van Tellingen Olaf
Department of Clinical Chemistry, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Huis, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Cancer Chemother Pharmacol. 2002 Feb;49(2):119-25. doi: 10.1007/s00280-001-0394-2. Epub 2001 Nov 20.
Recent studies in mice and patients have shown that the low oral bioavailability of paclitaxel can be increased by coadministration of P-glycoprotein blockers. However, in patients an increase in the oral paclitaxel dose from 60 to 300 mg/m(2) does not result in proportionally higher plasma levels. We hypothesized that the surfactant Cremophor EL, present in the formulation of paclitaxel, may be responsible for this nonlinear absorption by entrapping paclitaxel within the intestinal lumen, probably by inclusion in micelles.
Paclitaxel was administered to mdr1ab P-glycoprotein knockout mice with either the conventional (controls) or a seven-fold higher amount of Cremophor EL (test group). Plasma, gastrointestinal tissues with their contents and faeces were collected and analysed by high-performance liquid chromatography to determine the levels of paclitaxel and Cremophor EL. The critical micellar concentrations of Cremophor EL in the contents of the small intestine were also established by an in vitro assay.
Paclitaxel recoveries in the faeces of the control and test groups were 7.6% and 35.8%, respectively. The peak plasma level and plasma AUC were reduced in the test group by about 75% and 40%, respectively. Only in mice from the test group did substantial quantities of paclitaxel together with Cremophor EL reach the caecum, thus passing through the small intestine. The concentration of Cremophor EL in the distal part of the small intestine and the caecum was 15 times higher in the test group and well above the critical micellar concentration of Cremophor EL.
These results show that Cremophor EL prevents efficient uptake of paclitaxel from the gut, probably by entrapment within micelles. Other formulations should be developed for oral therapy with paclitaxel.
最近在小鼠和患者身上进行的研究表明，通过联合使用P-糖蛋白阻滞剂可提高紫杉醇的口服生物利用度。然而，在患者中，将口服紫杉醇剂量从60mg/m²增加到300mg/m²并不会导致血浆水平成比例升高。我们推测，紫杉醇制剂中含有的表面活性剂聚氧乙烯蓖麻油（Cremophor EL）可能是造成这种非线性吸收的原因，它可能通过将紫杉醇包裹在肠腔内（可能是通过形成胶束）来实现。
将紫杉醇分别给予多药耐药蛋白1ab（mdr1ab）P-糖蛋白基因敲除小鼠，一组给予常规剂量（对照组），另一组给予剂量高出7倍的Cremophor EL（试验组）。收集血浆、胃肠道组织及其内容物和粪便，采用高效液相色谱法进行分析，以测定紫杉醇和Cremophor EL的水平。还通过体外试验确定了小肠内容物中Cremophor EL的临界胶束浓度。
对照组和试验组小鼠粪便中紫杉醇的回收率分别为7.6%和35.8%。试验组的血浆峰值水平和血浆药时曲线下面积（AUC）分别降低了约75%和40%。只有试验组的小鼠有大量紫杉醇与Cremophor EL一起到达盲肠，从而通过了小肠。试验组小鼠小肠远端和盲肠中Cremophor EL的浓度高出15倍，且远高于Cremophor EL的临界胶束浓度。
这些结果表明，Cremophor EL可能通过包裹在胶束中而阻止了紫杉醇从肠道的有效吸收。应该开发其他制剂用于紫杉醇的口服治疗。
