Pgp-Mediated Interaction Between (R)-[11C]Verapamil and Tariquidar at the Human Blood-Brain Barrier: A Comparison With Rat Data.

Using positron emission tomography (PET) imaging we assessed, in vivo, the interaction between a microdose of (R)-[¹¹C]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)-[¹¹C]verapamil brain uptake (expressed as whole-brain volume of distribution (V_T)), with very similar half-maximum-effect concentrations. Both in humans and in rats, brain V_T 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 V_T 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]