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P‐glycoprotein overactivity in epileptogenic developmental lesions measured in vivo using (R)‐[ 11 C]verapamil PET
Author(s) -
IlyasFeldmann Maria,
Asselin MarieClaude,
Wang Shaonan,
McMahon Adam,
AntonRodriguez José,
Brown Gavin,
Hinz Rainer,
Duncan John S.,
Sisodiya Sanjay M.,
Koepp Matthias
Publication year - 2020
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.16581
Subject(s) - verapamil , statistical parametric mapping , epilepsy , lesion , positron emission tomography , medicine , p glycoprotein , in vivo , nuclear medicine , pharmacokinetics , pathophysiology , pharmacology , endocrinology , pathology , magnetic resonance imaging , chemistry , radiology , calcium , biology , multiple drug resistance , biochemistry , microbiology and biotechnology , psychiatry , antibiotics
Abstract Objective Overexpression of the drug transporter P‐glycoprotein (P‐gp) is thought to be involved in drug‐resistance in epilepsy by extrusion of antiepileptic drugs (AEDs). We used positron emission tomography (PET) and the P‐gp substrate radiotracer (R)‐[ 11 C]verapamil (VPM) together with the third‐generation P‐gp inhibitor tariquidar (TQD) to evaluate P‐gp function in individuals with drug‐resistant epileptogenic developmental lesions. Methods Twelve healthy controls (7 male, median age 45, range 35‐55 years), and two patients with epileptogenic developmental lesions (2 male, aged 24 and 62 years) underwent VPM‐PET scans before and 60 minutes after a 30‐minute infusion of 2 and 3 mg/kg TQD. The influx rate constant, VPM‐K 1 , was estimated from the first 10 minutes of dynamic data using a single‐tissue compartment model with a VPM plasma input function. Statistical parametric mapping (SPM) analysis was used to compare individual patients with the healthy controls. Results At baseline, SPM voxel‐based analysis revealed significantly lower uptake of VPM corresponding to the area of the epileptogenic developmental lesion compared to 12 healthy controls ( P < .048). This was accentuated following P‐gp inhibition with TQD. After TQD, the uptake of VPM was significantly lower in the area of the epileptogenic developmental lesion compared to controls ( P < .002). Significance This study provides further evidence of P‐gp overactivity in patients with drug‐resistant epilepsy, irrespective of the type of lesion. Identifying P‐gp overactivity as an underlying contributor to drug‐resistance in individual patients will enable novel treatment strategies aimed at overcoming or reversing P‐gp overactivity.