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Effect of the ABCB1 modulators elacridar and tariquidar on the distribution of paclitaxel in nude mice

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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.

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Abbreviations

ABCB1:

ABC transporter B1

BBB:

Blood–brain barrier

HIV:

Human immunodeficiency virus

HIP:

HIV protease inhibitor

MDR:

Multi drug resistance

p-gp:

P-glycoprotein 170

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Acknowledgments

The authors thank F. Wiesenmayer, O. Baumann and S. Bollwein for their excellent technical assistance.

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Correspondence to Armin Buschauer.

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Hubensack, M., Müller, C., Höcherl, P. et al. Effect of the ABCB1 modulators elacridar and tariquidar on the distribution of paclitaxel in nude mice. J Cancer Res Clin Oncol 134, 597–607 (2008). https://doi.org/10.1007/s00432-007-0323-9

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  • DOI: https://doi.org/10.1007/s00432-007-0323-9

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