Increased P-gp inhibition at the human blood brain barrier can be safely achieved by performing PET during peak plasma concentrations of tariquidar

Abstract

The permeability-glycoprotein (P-gp) efflux transporter is densely expressed at the blood-brain barrier (BBB) and its resultant 'spare capacity' requires substantial blockade to increase the uptake of avid substrates. This has blunted the ability of investigators to measure clinically meaningful alterations in P-gp function. This study, conducted in humans, examined two P-gp inhibitors (tariquidar, a known inhibitor, and disulfiram, a putative inhibitor) and two routes of administration (intravenous and oral) to maximally increase brain uptake of the avid and selective P-gp substrate ¹¹C-desmethyl-loperamide (dLop), while avoiding side effects associated with high doses of tariquidar. Methods: Forty-two ¹¹C-dLop positron emission tomography (PET) scans were obtained from 37 healthy volunteers. PET was performed with ¹¹C-dLop under five conditions: 1) injected under baseline conditions without P-gp inhibition; 2) injected one hour after IV tariquidar infusion; 3) injected during IV tariquidar infusion; 4) injected after oral tariquidar; and 5) injected after disulfiram. ¹¹C-dLop uptake was quantified with kinetic modeling using metabolite-corrected arterial input function or by measuring the area under the time-activity curve in brain from 10 to 30 minutes. Results: Neither oral tariquidar nor oral disulfiram increased brain uptake of ¹¹C-dLop. Injecting ¹¹C-dLop during tariquidar infusion, when plasma tariquidar concentrations 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. Injecting ¹¹C-dLop after tariquidar infusion also increased brain uptake, though higher doses (up to 6 mg/kg) were required. Brain uptake of ¹¹C-dLop increased fairly linearly with increasing plasma tariquidar concentrations, but we are uncertain whether maximal uptake was achieved. Conclusion: We sought to increase the dynamic range of P-gp function measured after blockade. Performing ¹¹C-dLop PET during peak plasma concentrations of tariquidar, achieved with concurrent administration of IV tariquidar, resulted in greater P-gp inhibition at the human BBB than delayed administration, and allowed use of a lower, more tolerable dose of tariquidar. Based on prior monkey studies, we suspect that plasma concentrations of tariquidar did not fully block P-gp; however, higher doses of tariquidar would likely be associated with unacceptable side effects.