P-glycoprotein over-activity and drug resistance in temporal lobe epilepsy

A major study published in this month's issue of Lancet Neurology, led by researchers at UCL's Institute of Neurology and funded by the EU-Framework 7 programme, provides the first in-vivo human evidence of an association between over-activity of P-glycoprotein  (a drug transporter) at the blood-brain barrier and drug resistance in temporal lobe epilepsy (TLE).

Drug resistance is an important clinical problem. Globally, 50,000,000 people have epilepsy: current treatments are ineffective in 30% of patients due to drug resistance. One generic mechanism for drug resistance, relevant for epilepsy and other brain disorders (e.g. depression, cancer, HIV) is over-activity of drug transporter(s) at the blood-brain-barrier, such as P-glycoprotein.

There is compelling evidence from animal models that P-glycoprotein over-activity prevents drugs from reaching therapeutic concentrations at their targets.

The research, which was part of EURIPIDES, a large consortium of basic scientists and clinical epileptologists co-oordinated by UCL, revealed that brain uptake of a P-glycoprotein biomarker ( [11C]verapamil PET) in drug-sensitive patients was higher than those in drug-resistant patients, suggesting that P-glycoprotein over-activity at the blood-brain barrier in drug-resistant patients results in lower drug concentrations in the brain.

The study looked for a change in biomarker brain uptake before and after administering a P-glycoprotein inhibitor (tariquidar) and showed that tariquidar-induced increases in brain uptake were attenuated in the sclerotic hippocampus (the brain area involved in TLE).

The findings correlate with those found in surgical temporal lobe specimens of patients who had undergone surgery, and are in keeping with the hypothesis that there is localized P-glycoprotein over-activity in drug-resistant TLE.

Professor Matthias Koepp, the Chief Investigator of EURIPIDES comments:

“Our study supports the hypothesis of multidrug transporter over-activity as an important mechanism for drug resistance in epilepsy. The availability of imaging biomarkers, such as [11C]verapamil PET, will support the development of new treatment strategies targeted at multidrug transporters and aimed at reversing drug resistance with selection of optimal patients and assessment of molecular targets.

Until now there has not been any conclusive way to detect the underlying mechanisms of drug-resistance, such as P-glycoprotein over-activity, and treat patients rationally. The stage is now set for direct translation to clinical trials. We have a tool to identify patients in whom P-glycoprotein over-activity could conceivably contribute to drug resistant epilepsy, and drugs, which can modulate or inhibit P-glycoprotein function.”

EURIPIDES was run from University College London and included 14 European research and hospital centres from UK, Netherlands, France, Germany, Denmark, Austria, Denmark and Greece. Drug-resistant and drug-sensitive patients with temporal lobe epilepsy and unilateral hippocampal sclerosis were recruited for this study from the National Hospital for Neurology & Neurosurgery and PET scans were performed at the Wolfson Molecular Imaging Centre in Manchester.

Read more:

Feldmann et al. (2013) P-glycoprotein expression and function in patients with temporal lobe epilepsy: a case-control study. Lancet Neurology, Volume 12, Issue 8, Pages 777–785.  DOI: 10.1016/S1474-4422(13)70109-1

EU Framework 7 programme : http://www.ucl.ac.uk/research/europe/funding