Functional Significance of Increased Drug Transporter Activity in Epilepsy

One hypothesized cause of drug resistance in medically refractory partial epilepsy is that up-regulation of multidrug transporters in the blood–brain barrier, such as P-glycoprotein, reduces effective concentrations of antiepileptic drugs (AEDs) in target tissue. These authors used (R)-[¹¹C]verapamil positron emission tomography (PET) kinetic modeling to compare P-glycoprotein activity in vivo in 8 seizure-free patients and 14 non–seizure-free patients with mesial temporal lobe epilepsy. They also compared the effect of P-glycoprotein inhibition (with tariquidar) in the non–seizure-free patients and 13 age-matched healthy controls.

At baseline, P-glycoprotein activity was significantly greater in non–seizure-free versus seizure-free patients in the ipsilateral amygdala, and bilateral parahippocampus, and fusiform, inferior temporal, and middle temporal gyri. Further, in the non-seizure-free group, seizure frequency correlated inversely and strongly with (R)-[¹¹C]verapamil K₁ (lower K₁ reflects greater P-glycoprotein activity in the form of efflux of substrate out of the brain). This relation was significant for whole brain (r=–0.651), and hippocampus (r=–0.604). After tariquidar administration, whole brain K₁ had significant, dose-dependent increases in non–seizure-free patients but not in controls. Regional analysis showed selective increased P-glycoprotein activity only in the ipsilateral hippocampus of non–seizure-free patients.