P-glycoprotein expression and function in patients with temporal lobe epilepsy: a case-control study

Maria Feldmann, Marie Claude Asselin, Joan Liu, Shaonan Wang, Adam McMahon, José Anton-Rodriguez, Matthew Walker, Mark Symms, Gavin Brown, Rainer Hinz, Julian Matthews, Martin Bauer, Oliver Langer, Maria Thom, Terry Jones, Christian Vollmar, John S. Duncan, Sanjay M. Sisodiya, Matthias J. Koepp

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Background: Studies in rodent models of epilepsy suggest that multidrug efflux transporters at the blood-brain barrier, such as P-glycoprotein, might contribute to pharmacoresistance by reducing target-site concentrations of antiepileptic drugs. We assessed P-glycoprotein activity in vivo in patients with temporal lobe epilepsy. Methods: We selected 16 patients with pharmacoresistant temporal lobe epilepsy who had seizures despite treatment with at least two antiepileptic drugs, eight patients who had been seizure-free on antiepileptic drugs for at least a year after 3 or more years of active temporal lobe epilepsy, and 17 healthy controls. All participants had a baseline PET scan with the P-glycoprotein substrate (R)-[11C]verapamil. Pharmacoresistant patients and healthy controls then received a 30-min infusion of the P-glycoprotein-inhibitor tariquidar followed by another (R)-[11C]verapamil PET scan 60 min later. Seizure-free patients had a second scan on the same day, but without tariquidar infusion. Voxel-by-voxel, we calculated the (R)-[11C]verapamil plasma-to-brain transport rate constant, K1 (mL/min/cm3). Low baseline K1 and attenuated K1 increases after tariquidar correspond to high P-glycoprotein activity. Findings: Between October, 2008, and November, 2011, we completed (R)-[11C]verapamil PET studies in 14 pharmacoresistant patients, eight seizure-free patients, and 13 healthy controls. Voxel-based analysis revealed that pharmacoresistant patients had lower baseline K1, corresponding to higher baseline P-glycoprotein activity, than seizure-free patients in ipsilateral amygdala (0·031 vs 0·036 mL/min/cm3; p=0·014), bilateral parahippocampus (0·032 vs 0·037; p
    Original languageEnglish
    Pages (from-to)777-785
    Number of pages8
    JournalThe Lancet Neurology
    Volume12
    Issue number8
    DOIs
    Publication statusPublished - 18 Jun 2013

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