1. Pgp-Mediated Interaction Between (R)-[11C]Verapamil and Tariquidar at the Human Blood-Brain Barrier: A Comparison With Rat Data.
- Author
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Bauer, M, Zeitlinger, M, Karch, R, Matzneller, P, Stanek, J, Jäger, W, Böhmdorfer, M, Wadsak, W, Mitterhauser, M, Bankstahl, J P, Löscher, W, Koepp, M, Kuntner, C, Müller, M, and Langer, Oliver
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VERAPAMIL ,BLOOD-brain barrier ,LABORATORY rats ,POSITRON emission tomography ,HUMAN research subjects ,HUMAN beings - Abstract
Using positron emission tomography (PET) imaging we assessed, in vivo, the interaction between a microdose of (R)-[
11 C]verapamil (a P-glycoprotein (Pgp) substrate) and escalating doses of the Pgp inhibitor tariquidar (3, 4, 6, and 8 mg/kg) at the blood-brain barrier (BBB) in healthy human subjects. We compared the dose-response relationship of tariquidar in humans with data obtained in rats using a similar methodology. Tariquidar was equipotent in humans and rats in its effect of increasing (R)-[11 C]verapamil brain uptake (expressed as whole-brain volume of distribution (VT )), with very similar half-maximum-effect concentrations. Both in humans and in rats, brain VT approached plateau levels at plasma tariquidar concentrations >1,000 ng/ml. However, Pgp inhibition in humans led to only a 2.7-fold increase in brain VT relative to baseline scans (before administration of tariquidar) as compared with 11.0-fold in rats. The results of this translational study add to the accumulating evidence that there are marked species-dependent differences in Pgp expression and functionality at the BBB. [ABSTRACT FROM AUTHOR]- Published
- 2012
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