Pgp-mediated interaction between (R)-[11C]verapamil and tariquidar at the human blood-brain barrier: a comparison with rat data

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 (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.

Figure 1

Mean time-activity curves (standardized uptake value, SUV ±standard deviation, SD) of unmetabolized (R)-[¹¹C]verapamil in arterial plasma from 3.5 to 40 min after radiotracer injection for baseline scans (i.e. without tariquidar administration, n=5) and scans after administration of 2 mg/kg tariquidar (n=5) and from 3.5 to 60 min after radiotracer injection for scans after administration of 3, 4, 6 and 8 mg/kg tariquidar (n=3 per dose group).

Figure 2

Representative transaxial MRIs merged with (R)-[¹¹C]verapamil PET summation images (0-40 min) for a baseline scan (a, taken from reference (17)) and scans after administration of tariquidar at a dose of 3 mg/kg (b) and 8 mg/kg (c). Activity concentration is expressed as standardized uptake value (SUV) and radiation scale is set from 0.1 to 3.0. Anatomical structures are labeled using white arrows (v, ventricle; p, choroid plexus; s, venous sinus).

Figure 3

Mean time-activity curves (standardized uptake value, SUV±SD) of (R)-[¹¹C]verapamil in whole brain grey matter from 0 to 40 min after radiotracer injection for baseline scans (i.e. without tariquidar administration, n=5) and scans after administration of 2 mg/kg tariquidar (n=5) and from 0 to 60 min after radiotracer injection for scans after administration of 3, 4, 6 and 8 mg/kg tariquidar (n=3 per dose group).

Figure 4

Relationship between tariquidar plasma levels (ng/mL) at the end of the PET scan and (R)-[¹¹C]verapamil whole brain volume of distribution V_T-V_T at baseline and influx rate constant K₁-K₁ at baseline derived from 2-tissue-4-rate constant compartment model from 0-40 min in humans (a, b) and from 0-60 min in Sprague-Dawley rats (c,d) (19) and corresponding sigmoidal fits using the Hill function.