Functional Significance of Increased Drug Transporter Activity in Epilepsy

Summary and Comment |
September 20, 2013

Functional Significance of Increased Drug Transporter Activity in Epilepsy

  1. Robert C. Knowlton, MD, MSPH

A small study shows a localized increase in P-glycoprotein activity in vivo in patients with drug-resistant temporal lobe epilepsy, specifically in epileptogenic tissue.

  1. Robert C. Knowlton, MD, MSPH

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.


This meticulous work provides convincing evidence for derangements in a key multidrug blood–brain barrier transporter that are specific to patients with medically intractable epilepsy and to brain regions involved in seizure generation. The solid correlation of increased transporter activity with higher seizure frequency may help clarify observations about intrinsic seizure intervals and prognosis for antiepileptic drug efficacy. Most important, this work is provocative for further pursuing the transporter hypothesis. One of the first issues to address will be determining the differential affinity of various AEDs for P-glycoprotein and the effect of transporter manipulations on clinically significant drug concentrations. If confirmed, even as just one of multiple factors, this mechanism of drug resistance could have very important implications for improved treatment of the nearly one third of epilepsy patients whose seizures remain uncontrolled despite multiple AED trials.

Editor Disclosures at Time of Publication

  • Disclosures for Robert C. Knowlton, MD, MSPH at time of publication Grant / research support NIH-NINDS Leadership positions in professional societies Southern Epilepsy and EEG Society (Treasurer)


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