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BMC Pharmacology

, 7:A22 | Cite as

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

  • Oliver Langer
  • Jens Bankstahl
  • Claudia Kuntner
  • Aiman Abrahim
  • Rudolf Karch
  • Johann Stanek
  • Thomas Wanek
  • Maria Zsebedics
  • Kurt Kletter
  • Wolfgang Löscher
  • Markus Müller
  • Herbert Kvaternik
Open Access
Meeting abstract
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Keywords

Confidence Interval Positron Emission Tomography Potential Application Verapamil Effective Dose 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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. 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.CrossRefPubMedGoogle Scholar

Copyright information

© Langer et al; licensee BioMed Central Ltd. 2007

This article is published under license to BioMed Central Ltd.

Authors and Affiliations

  • Oliver Langer
    • 1
    • 2
  • Jens Bankstahl
    • 1
  • Claudia Kuntner
    • 1
  • Aiman Abrahim
    • 1
    • 2
  • Rudolf Karch
    • 3
  • Johann Stanek
    • 1
  • Thomas Wanek
    • 1
  • Maria Zsebedics
    • 1
  • Kurt Kletter
    • 4
  • Wolfgang Löscher
    • 5
  • Markus Müller
    • 2
  • Herbert Kvaternik
    • 1
  1. 1.Department of RadiopharmaceuticalsARCGmbHSeibersdorfAustria
  2. 2.Department of Clinical PharmacologyMedical University of ViennaAustria
  3. 3.Department of Medical Computer SciencesMedical University of ViennaAustria
  4. 4.Department of Nuclear MedicineMedical University of ViennaAustria
  5. 5.Department of Pharmacology, Toxicology and PharmacySchool of Veterinary Medicine HannoverGermany

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