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

  • Martina Hubensack
  • Christine Müller
  • Peter Höcherl
  • Stephan Fellner
  • Thilo Spruss
  • Günther Bernhardt
  • Armin Buschauer
Original Paper

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.

Keywords

Blood brain barrier ABCB1 P-glycoprotein 170 Valspodar Elacridar Tariquidar Paclitaxel 

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

Notes

Acknowledgments

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

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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Martina Hubensack
    • 1
  • Christine Müller
    • 1
  • Peter Höcherl
    • 1
  • Stephan Fellner
    • 1
  • Thilo Spruss
    • 1
  • Günther Bernhardt
    • 1
  • Armin Buschauer
    • 1
  1. 1.Institute of PharmacyUniversity of RegensburgRegensburgGermany

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