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. doi: 10.1007/s00432-007-0323-9. Epub 2007 Oct 12.


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.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP-Binding Cassette Transporters / drug effects*
  • Acridines / pharmacokinetics*
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics*
  • Brain / metabolism
  • Chromatography, High Pressure Liquid
  • Drug Interactions
  • Flow Cytometry
  • Mice
  • Mice, Nude
  • Paclitaxel / pharmacokinetics*
  • Quinolines / pharmacokinetics*
  • Tetrahydroisoquinolines / pharmacokinetics*


  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP-Binding Cassette Transporters
  • Acridines
  • Quinolines
  • Tetrahydroisoquinolines
  • Abcb1b protein, mouse
  • tariquidar
  • Elacridar
  • Paclitaxel