Feldmann, M; (2015) Imaging p-glycoprotein function: prediction of treatment response in mesial temporal lobe epilepsy. Doctoral thesis , UCL (University College London).

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Abstract

Background: Overexpression of multidrug efflux transporters at the blood–brain barrier, such as P-glycoprotein (Pgp), might contribute to pharmacoresistance by reducing target-site concentrations of antiepileptic drugs (AEDs). We assessed Pgp activity in vivo in patients with mesial temporal lobe epilepsy (mTLE). / Methods: Fourteen pharmacoresistant mTLE patients with unilateral hippocampal sclerosis (HS), three patients with pharmacoresistant epilepsy due to focal cortical dysplasia (FCD), eight seizure-free mTLE patients and 13 healthy controls underwent baseline PET scans with the Pgp substrate (R)- [¹¹C]verapami (VPM). Pharmacoresistant mTLE patients and healthy controls underwent a second VPM PET scan following infusion of the Pgp-inhibitor tariquidar (TQD). The transfer rate constant from plasma to brain, K1, was estimated using a single-tissue compartment model with a VPM-in-plasma arterial input function. Analysis was performed on the first 10min of dynamic data containing limited radiolabeled metabolites. Regions were defined automatically using a brain atlas (ROI analysis), and ratios of VPM-K1 values were calculated between a reference region (parietal cortex) and target regions. Parametric maps of VPM-K1 were also generated using generalised linear least squares and was used for SPM voxel-based analysis. For the voxel-based analysis at baseline we created VPM PET images corrected for differences in whole brain radiotracer uptake. Furthermore, we compared VPM PET scans with epileptic tissues removed during epilepsy surgery and measured peripheral markers of Pgp function: PBMC ABCB1 mRNA, ABCB1 polymorphism and S100B. / Findings: The ROI analysis revealed differences in VPM metabolism between mTLE patients and healthy controls which is caused by AED-mediated hepatic cytochrome P450 enzyme induction in mTLE patients requiring images to be normalised for global brain differences. When using ROI analysis and normalised VPM ratios there was no difference in VPM-K1 ratios in pharmacoresistant compared to seizure-free mTLE patients or healthy controls. The ROI analysis after partial Pgp-inhibition with TQD showed attenuated global increases of VPM brain uptake in pharmacoresistant mTLE patients compared to healthy controls but there where no regional differences. The voxel-based analysis at baseline revealed that pharmacoresistant mTLE patients had reduced VPM uptake compared to seizure-free mTLE patients and healthy controls in ipsi- and contralateral temporal lobes. Higher Pgp activity was associated with higher seizure frequency. After Pgp-inhibition with TQD pharmacoresistant mTLE patients had reduced increases of VPM brain uptake in the whole brain and ipsilateral hippocampus, implicating Pgp overactivity in the epileptogenic hippocampus. The difference in percentage change in VPM brain uptake after Pgp-inhibition with TQD inversely correlated with the difference in percentage area of Pgp immunopositive labeling in pharmacoresistant mTLE patients who underwent epilepsy surgery. Pharmacoresistant epilepsy patients with FCD had reduced VPM brain uptake in close proximity to the area of FCD but also extending to other ipsilateral regions. There were no differences in peripheral markers of Pgp function between the three groups. Our results support the hypothesis of Pgp overactivity in pharmacoresistant epilepsy.

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