Journal Article

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

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

2013

Overview

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. 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. 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<0·0001), fusiform gyrus (0·036 vs 0·041; p<0·0001), inferior temporal gyrus (0·035 vs 0·041; p<0·0001), and middle temporal gyrus (0·038 vs 0·044; p<0·0001). Higher P-glycoprotein activity was associated with higher seizure frequency in whole-brain grey matter (p=0·016) and the hippocampus (p=0·029). In healthy controls, we noted a 56·8% increase of whole-brain K1 after 2 mg/kg tariquidar, and 57·9% for 3 mg/kg; in patients with pharmacoresistant temporal lobe epilepsy, whole-brain K1 increased by only 21·9% for 2 mg/kg and 42·6% after 3 mg/kg. This difference in tariquidar response was most pronounced in the sclerotic hippocampus (mean 24·5% increase in patients vs mean 65% increase in healthy controls, p<0·0001). Our results support the hypothesis that there is an association between P-glycoprotein overactivity in some regions of the brain and pharmacoresistance in temporal lobe epilepsy. If this relation is confirmed, and P-glycoprotein can be identified as a contributor to pharmacoresistance, overcoming P-glycoprotein overactivity could be investigated as a potential treatment strategy. EU-FP7 programme (EURIPIDES number 201380).

• Publisher: Elsevier Ltd,Elsevier Limited
• Subject: Adolescent / Adult / Analysis of Variance / ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism / Blood-brain barrier / Brain research / Calcium Channel Blockers - pharmacokinetics / Carbon Isotopes - pharmacokinetics / Case-Control Studies / Convulsions & seizures / Drug dosages / Epilepsy / Epilepsy, Temporal Lobe - diagnostic imaging / Epilepsy, Temporal Lobe - metabolism / Epilepsy, Temporal Lobe - pathology / Female / Glycoproteins / Hippocampus - diagnostic imaging / Hippocampus - metabolism / Humans / Male / Metabolism / Metabolites / Middle Aged / Neurology / Plasma / Positron-Emission Tomography / Retrospective Studies / Rodents / Verapamil - pharmacokinetics / Young Adult