Increased Permeability-Glycoprotein Inhibition at the Human Blood–Brain Barrier Can Be Safely Achieved by Performing PET During Peak Plasma Concentrations of Tariquidar

Journal of Nuclear Medicine

Robert B. Innis¹  Ritwik Bhatia¹  Victor W. Pike¹  Alicia E. Woock¹  Cheryl L. Morse¹  Sami S. Zoghbi¹  H. Umesha Shetty¹  William C. Kreisl¹ 

关键词: P-glycoprotein (P-gp);    positron emission tomography (PET);    N-desmethyl-loperamide;    tariquidar;   

DOI  :  10.2967/jnumed.114.146894

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

The permeability-glycoprotein (P-gp) efflux transporter is densely expressed at the blood–brain barrier, and its resultant spare capacity requires substantial blockade to increase the uptake of avid substrates, blunting the ability of investigators to measure clinically meaningful alterations in P-gp function. This study, conducted in humans, examined 2 P-gp inhibitors (tariquidar, a known inhibitor, and disulfiram, a putative inhibitor) and 2 routes of administration (intravenous and oral) to maximally increase brain uptake of the avid and selective P-gp substrate 11C-N-desmethyl-loperamide (dLop) while avoiding side effects associated with high doses of tariquidar. Methods: Forty-two 11C-dLop PET scans were obtained from 37 healthy volunteers. PET was performed with 11C-dLop under the following 5 conditions: injected under baseline conditions without P-gp inhibition, injected 1 h after intravenous tariquidar infusion, injected during intravenous tariquidar infusion, injected after oral tariquidar, and 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 the brain from 10 to 30 min. 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 a brain uptake of the radioligand approximately 5-fold greater than baseline. Brain uptake was similar with 2 and 4 mg of intravenous tariquidar per kilogram; 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 intravenous tariquidar, resulted in greater P-gp inhibition at the human blood–brain barrier than delayed administration and allowed the use of a lower, more tolerable dose of tariquidar. On the basis of 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.

【 授权许可】

Unknown