A PET microdosing study with the P-glycoprotein inhibitor tariquidar

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.

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 (AUC_{0–60 brain}/AUC_{0–60 plasma}).

Brain activity uptake was low after injection of [¹¹C]tariquidar with a mean AUC_{0–60 brain}/AUC_{0–60 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.

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.

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).

Affiliations

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

   • Martin Bauer
   • , Markus Zeitlinger
   • , Johann Stanek
   • , Markus Müller
   •  & Oliver Langer

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

   • Cécile Philippe
   • , Wolfgang Wadsak
   • , Markus Mitterhauser
   •  & Georgios Karanikas

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

   • Johann Stanek
   •  & Oliver Langer

Corresponding author

Correspondence to Oliver Langer.

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