P-glycoprotein overactivity in epileptogenic developmental lesions measured in vivo using (R)-[11 C]verapamil PET.
Epilepsia
; 61(7): 1472-1480, 2020 07.
Article
in En
| MEDLINE
| ID: mdl-32627849
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-K1 , 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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Carbon Radioisotopes
/
Verapamil
/
ATP Binding Cassette Transporter, Subfamily B, Member 1
/
Positron-Emission Tomography
/
Drug Resistant Epilepsy
Type of study:
Prognostic_studies
Limits:
Adult
/
Female
/
Humans
/
Male
/
Middle aged
Language:
En
Journal:
Epilepsia
Year:
2020
Document type:
Article
Affiliation country:
United kingdom