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This article is part of the supplement: 18th Scientific Symposium of the Austrian Pharmacological Society (APHAR)

Open Access Meeting abstract

A PET microdosing study with the P-glycoprotein inhibitor tariquidar

Martin Bauer1, Markus Zeitlinger1, Cécile Philippe2, Johann Stanek13, Wolfgang Wadsak2, Markus Mitterhauser2, Georgios Karanikas2, Markus Müller1 and Oliver Langer13*

Author Affiliations

1 Department of Clinical Pharmacology, Medical University of Vienna, 1090 Vienna, Austria

2 Department of Nuclear Medicine, Medical University of Vienna, 1090 Vienna, Austria

3 Health and Environment Department, AIT Austrian Institute of Technology GmbH, 2444 Seibersdorf, Austria

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BMC Pharmacology and Toxicology 2012, 13(Suppl 1):A17  doi:10.1186/2050-6511-13-S1-A17

The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/2050-6511/13/S1/A17


Published:17 September 2012

© 2012 Bauer et al; licensee BioMed Central Ltd.

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

Background

The adenosine triphosphate-binding cassette transporters P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) restrict absorption and body distribution and promote excretion of several clinically used drugs. Tariquidar (XR9576) is a potent third-generation dual Pgp and BCRP inhibitor, which is currently tested in clinical trials to overcome chemoresistance of tumors and to enhance brain distribution of Pgp/BCRP substrate drugs. We performed a positron emission tomography (PET) microdosing study with carbon-11-labelled tariquidar ([11C]tariquidar) which aimed at assessing the brain distribution of [11C]tariquidar in healthy volunteers.

Methods

Six healthy subjects received an i.v. bolus injection of approximately 400 MBq of [11C]tariquidar containing less than 30 µg of unlabelled tariquidar. Then, dynamic brain PET scans and arterial blood sampling were performed. Radiolabelled metabolites of [11C]tariquidar in plasma were measured with a solid-phase extraction/HPLC assay. Brain activity uptake was expressed as the ratio of the area under the whole brain grey matter time-activity curve to the area under the plasma time-activity curve from time 0 to 60 min (AUC0–60 brain/AUC0–60 plasma).

Results

Brain activity uptake was low after injection of [11C]tariquidar with a mean AUC0–60 brain/AUC0–60 plasma of 0.14 ± 0.03. At 60 min after radiotracer injection, 78 ± 12% of total radioactivity in plasma was in the form of unchanged parent radiotracer. Less than 1% of the total injected dose excreted in urine over 90 min.

Conclusions

Low brain uptake of radioactivity is consistent with tariquidar being, at microdoses, a dual substrate of Pgp and BCRP. [11C]Tariquidar PET after inhibition of Pgp with unlabelled tariquidar may be a promising approach to selectively assess BCRP function at the human blood-brain barrier.

Acknowledgements

Funded by the European Community’s Seventh Framework Program (grant agreement 201380 (Euripides)) and Austrian Science Fund (FWF) project ”Transmembrane Transporters in Health and Disease” (SFB F35).