%0 Journal Article
%T Pharmacokinetic modeling of P-glycoprotein function at the rat and human blood¨Cbrain barriers studied with (R)-[11C]verapamil positron emission tomography
%A Julia M¨¹llauer
%A Claudia Kuntner
%A Martin Bauer
%A Jens P Bankstahl
%A Markus M¨¹ller
%A Rob A Voskuyl
%A Oliver Langer
%A Stina Syv£¿nen
%J EJNMMI Research
%D 2012
%I Springer
%R 10.1186/2191-219x-2-58
%X Data obtained from a preclinical and clinical study, in which paired (R)-[11C]verapamil PET scans were performed before, during, and after tariquidar administration, were analyzed using nonlinear mixed effects (NLME) modeling. Administration of tariquidar was included as a covariate on the influx and efflux parameters (Qin and Qout) in order to investigate if tariquidar increased influx or decreased outflux of radiotracer across the blood¨Cbrain barrier (BBB). Additionally, the influence of pilocarpine-induced status epilepticus (SE) was tested on all model parameters, and the brain-to-plasma partition coefficient (VT-NLME) was calculated.Our model indicated that tariquidar enhances brain uptake of (R)-[11C]verapamil by decreasing Qout. The reduction in Qout in rats during and immediately after tariquidar administration (sevenfold) was more pronounced than in the second PET scan acquired 2 h after tariquidar administration (fivefold). The effect of tariquidar on Qout in humans was apparent during and immediately after tariquidar administration (twofold reduction in Qout) but was negligible in the second PET scan. SE was found to influence the pharmacological volume of distribution of the central brain compartment Vbr1. Tariquidar treatment lead to an increase in VT-NLME, and pilocarpine-induced SE lead to increased (R)-[11C]verapamil distribution to the peripheral brain compartment.Using NLME modeling, we were able to provide mechanistic insight into the effects of tariquidar and SE on (R)-[11C]verapamil transport across the BBB in control and 48 h post SE rats as well as in humans.About one-third of patients with epilepsy are pharmacoresistant and do not respond adequately to antiepileptic drug therapy [1]. The blood¨Cbrain barrier (BBB) has a major role in regulating the transport of antiepileptic drugs to their target site of action. Drug penetration across the BBB is influenced by several mechanisms, such as passive diffusion, active influx, and active efflux. Reg
%K Nonlinear mixed effects modeling
%K Positron emission tomography
%K (R)-[11C]verapamil
%K P-glycoprotein
%K Tariquidar
%K Pilocarpine-induced epilepsy
%K Species differences
%U http://www.ejnmmires.com/content/2/1/58