Imaging of P-glycoprotein-mediated pharmacoresistance in the hippocampus: Proof-of-concept in a chronic rat model of temporal lobe epilepsy

Abstract

Purpose: Based on experimental findings, overexpression of P-glycoprotein at the blood-brain barrier has been suggested to be a contributor to pharmacoresistance of the epileptic brain. We test a technique for evaluation of interindividual differences of elevated transporter function, through microPET analysis of the impact of the P-glycoprotein modulator tariquidar. The preclinical study is intended for eventual translation to clinical research of patients with pharmacoresistant seizure disorders. Methods: We made a microPET evaluation of the effects of tariquidar on the brain kinetics of the P-glycoprotein substrate [18F]MPPF in a rat model with spontaneous recurrent seizures, in which it has previously been demonstrated that phenobarbital nonresponders exhibit higher P-glycoprotein expression than do phenobarbital responders. Results: Mean baseline parametric maps of the [ 18F]MPPF unidirectional blood-brain clearance (K1; ml/g per min) and the efflux rate constant (k2; per min) did not differ between the nonresponder and responder group. Tariquidar pretreatment increased the magnitude of [18F]MPPF K1 in hippocampus by a mean of 142% in the nonresponders, which significantly exceeded the 92% increase observed in the responder group. The same treatment decreased the mean magnitude of [18F]MPPF k2 in hippocampus by 27% in nonresponders, without comparable effects in the responder group. Discussion: These results constitute a proof-of-concept for a novel imaging approach to evaluate blood-brain barrier P-glycoprotein function in animals. By extension, [ 18F]MPPF positron emission tomography (PET) with tariquidar pretreatment may be amenable for clinical applications exploring further the relevance of P-glycoprotein overexpression, and for enabling the rational design of pharmacotherapy according to individual differences in P-glycoprotein expression. © 2010 International League Against Epilepsy.