Effect of the ABCB1 modulators elacridar and tariquidar on the distribution of paclitaxel in nude mice.
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Hubensack M, Muller C, Hocherl P, Fellner S, Spruss T, Bernhardt G, Buschauer A
Effect of the ABCB1 modulators elacridar and tariquidar on the distribution of paclitaxel in nude mice.
J Cancer Res Clin Oncol. 2008 May;134(5):597-607. Epub 2007 Oct 12.
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- 17932689 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
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- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Elacridar P-glycoprotein 1 Protein Humans UnknownNot Available Details