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Background  This study investigated the influence of P-glycoprotein (P-gp) inhibitor tariquidar on the pharmacokinetics of P-gp substrate radiotracer ( R )-[ 11 C]verapamil in plasma and brain of rats and humans by means of positron emission tomography (PET).    Methods  Data obtained from a preclinical and clinical study, in which paired ( R )-[ 11 C]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 ( Q  in  and  Q  out ) in order to investigate if tariquidar increased influx or decreased outflux of radiotracer across the blood–brain barrier (BBB). Additionally, the influence of pilocarpine-induced status epilepticus (SE) was tested on all model parameters, and the brain-to-plasma partition coefficient ( V  T-NLME ) was calculated.    Results  Our model indicated that tariquidar enhances brain uptake of ( R )-[ 11 C]verapamil by decreasing  Q  out . The reduction in  Q  out  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  Q  out  in humans was apparent during and immediately after tariquidar administration (twofold reduction in  Q  out ) but was negligible in the second PET scan. SE was found to influence the pharmacological volume of distribution of the central brain compartment  V  br1 . Tariquidar treatment lead to an increase in  V  T-NLME , and pilocarpine-induced SE lead to increased ( R )-[ 11 C]verapamil distribution to the peripheral brain compartment.    Conclusions  Using NLME modeling, we were able to provide mechanistic insight into the effects of tariquidar and SE on ( R )-[ 11 C]verapamil transport across the BBB in control and 48 h post SE rats as well as in humans.

ejnmmi research

Pharmacokinetic modeling of P-glycoprotein function at the rat and human blood–brain barriers studied with (R)-[11C]verapamil positron emission tomography