Abstract
1801
Objectives The permeability-glycoprotein (P-gp) efflux transporter acts at high capacity to completely block brain entry of avid substrates, including radiolabeled substrates. Intravenous (IV) administration of tariquidar, a P-gp inhibitor, increases brain uptake of the substrate PET radiotracer 11C-dLop. This study sought to identify a method of P-gp inhibition that would allow for reliable positron emission tomography (PET) measurement of P-gp inhibition, but avoid the side effects associated with high tariquidar doses.
Methods PET was performed in healthy volunteers with 11C-dLop injected either 1) under baseline conditions, 2) one hour after IV infusion of tariquidar (4 or 6 mg/kg), 3) during IV infusion of tariquidar (2 or 4 mg/kg), or 4) after 1500 mg oral tariquidar. 11C-dLop uptake was quantified by measuring the area under the time-activity curve in brain from 10 to 30 minutes. Ten subjects had plasma concentration of tariquidar measured using liquid chromatography/mass spectrometry.
Results Injecting 11C-dLop after tariquidar infusion resulted in brain uptake of radioligand approximately two- to four-fold greater than baseline. Injecting 11C-dLop during tariquidar infusion, when plasma concentrations of tariquidar reach their peak, resulted in brain uptake of radioligand approximately five-fold greater than baseline. Brain uptake was similar with 2 and 4 mg/kg IV tariquidar; however, the lower dose was better tolerated. Oral tariquidar did not increase brain uptake of 11C-dLop, likely due to low plasma concentrations of tariquidar. The half-maximum-effect concentration of tariquidar (1045 ng/mL) was similar to plasma concentrations of subjects who had 11C-dLop injected during 2 mg/kg tariquidar infusion (1046 ± 449 ng/mL).
Conclusions Performing 11C-dLop PET during peak plasma concentrations of tariquidar, with concurrent administration of 2 mg/kg IV tariquidar, results in safe and reliable measurement of P-gp inhibition.
Research Support This research was supported by the NIMH Intramural Research Program.