Effect of the ABCB1 modulators elacridar and tariquidar on the distribution of paclitaxel in nude mice
Effect of the ABCB1 modulators elacridar and tariquidar on the distribution of paclitaxel in nude mice
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DOI：
10.1007/s00432-007-0323-9
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发表时间：
2008-05-01
影响因子：
3.6
通讯作者：
Buschauer, Armin
中科院分区：
文献类型：
--
作者：
Hubensack, Martina;Mueller, Christine;Buschauer, Armin
目的我们研究了紫杉醇与第二代ABCB 1（p-gp）调节剂伐司泊达联合应用对裸鼠脑内人U118-MG胶质母细胞瘤生长的影响。伐司泊达通过抑制血脑屏障表达的p-gp，显著增加紫杉醇的脑水平。因此，肿瘤负荷降低了90%，这被认为是概念验证。然而，由于外周组织中p-gp调节导致药物水平升高，因此必须降低紫杉醇剂量。因此，在本研究中，我们研究了紫杉醇与第三代ABCB 1调节剂依克立达和tariquidar的共同应用，这应该是优先调节p-gp在脑毛细血管。方法通过流式细胞术和体外化疗敏感性测定的抑制活性的调节剂。为了确定紫杉醇在体内的分布，裸鼠接受50 mg/kg伐司泊达、依克立达或tariquidar p.o.（对照：媒介物）静脉内注射8 mg/kg紫杉醇前4小时。结果我们的体外实验表明，与伐司泊达相比，新的调节剂的有效性约为80倍。紫杉醇与依克立达和tariquidar的联合给药导致脑中细胞生长抑制剂浓度的长期持续五倍增加。虽然增加（2.5至7倍）往往是较低的共同管理的valspodar（6至8倍）诱导相比，脑/血浆比实现与新的modulators是2-15倍higher.Conclusions依克立达和tariquidar似乎调节P-糖蛋白优先在血脑屏障。我们的研究结果表明，细胞抑制剂与依克立达或tariquidar组合的全身毒性应低于与伐司泊达组合。
Purpose Previously, we studied the effect of co-administration of paclitaxel with the second generation ABCB1 (p-gp) modulator valspodar on the intracerebral growth of human U118-MG glioblastoma in nude mice. Valspodar significantly increased the brain levels of paclitaxel by inhibition of p-gp expressed at the blood brain barrier. Thus, the tumour burden was reduced by 90%, which was considered as a proof of concept. However, the paclitaxel dose had to be reduced because of toxic side effects resulting from increased drug levels due to p-gp modulation in peripheral tissues. Therefore, in the present study we examined the co-application of paclitaxel with the third generation ABCB1 modulators elacridar and tariquidar, which were supposed to preferentially modulate p-gp in brain capillaries.Methods The inhibitory activity of the modulators was measured by a flow cytometric and a chemosensitivity assay in vitro. To determine the distribution of paclitaxel in vivo, nude mice received 50 mg/kg of valspodar, elacridar or tariquidar p.o. (control: vehicle) 4 h before i.v. injection of 8 mg/kg of paclitaxel. Brain, liver, kidney and plasma were collected and analyzed by RP-HPLC.Results Our in vitro experiments demonstrate that the new modulators are about 80 times more effective in comparison to valspodar. Co-administration of paclitaxel with elacridar and tariquidar led to a long lasting fivefold increase in the concentration of the cytostatic in the brain. Although the increase (2.5- to 7-fold) tended to be lower compared to that induced by co-administered valspodar (six- to eightfold), the brain/plasma ratios achieved with the new modulators were 2-15 times higher.Conclusions Elacridar and tariquidar seem to modulate p-glycoprotein preferentially at the blood-brain barrier. Our results suggest that the systemic toxicity of cytostatics combined with elacridar or tariquidar should be lower than in combination with valspodar.