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In vivo dose finding of tariquidar using (R)-[11C]verapamil μPET

Introduction

Tariquidar (TQD, Xenova, UK) is a third-generation inhibitor of the multidrug efflux transporter P-glycoprotein (P-gp) with potential applications in neurology and oncology in order to increase drug exposure of tissues targeted for treatment. We used small-animal positron emission tomography (μPET) with the P-gp substrate (R)-[11C]verapamil (VPM) in order to measure in vivo the degree of P-gp inhibition at the rat blood-brain barrier (BBB) after administration of different doses of TQD.

Methods

Wistar Unilever rats received intravenous doses of 0, 1, 3, 5, 7.5 and 15 mg/kg of TQD followed by a 1-hour VPM μPET scan recorded at 2 hours after TQD administration. Brain-to-plasma radioactivity ratios were fitted to a sigmoidal dose-response curve.

Results

TQD inhibited P-gp-mediated efflux of VPM across the BBB with an apparent half-maximum effective dose (ED50) of 6.6 mg/kg (95% confidence interval: 4.9–8.2 mg/kg) which was in good agreement with previous data reported in mice for another P-gp substrate (loperamide, ED50: 5.7 mg/kg) [1]. Brain-to-plasma radioactivity ratios after 0 and 15 mg/kg of TQD were 0.23 and 3.15, respectively.

Conclusion

Our data suggest that TQD is a potent inhibitor of P-gp at the rat BBB. Moreover, VPM PET appears to be a useful tool for in vivo dose finding of novel P-gp inhibitors in animals and humans.

References

  1. Choo EF, Kurnik D, Muszkat M, Ohkubo T, Shay SD, Higginbotham JN, Glaeser H, Kim RB, Wood AJ, Wilkinson GR: Differential in vivo sensitivity to inhibition of P-glycoprotein located in lymphocytes, testes, and the blood-brain barrier. J Pharmacol Exp Ther. 2006, 317: 1012-1018. 10.1124/jpet.105.099648.

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Correspondence to Oliver Langer.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Langer, O., Bankstahl, J., Kuntner, C. et al. In vivo dose finding of tariquidar using (R)-[11C]verapamil μPET. BMC Pharmacol 7, A22 (2007). https://doi.org/10.1186/1471-2210-7-S2-A22

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  • DOI: https://doi.org/10.1186/1471-2210-7-S2-A22

Keywords

  • Confidence Interval
  • Positron Emission Tomography
  • Potential Application
  • Verapamil
  • Effective Dose