The multidrug transporter hypothesis of drug resistance in epilepsy: Proof-of-principle in a rat model of temporal lobe epilepsy

Neurobiol Dis. 2006 Oct;24(1):202-11. doi: 10.1016/j.nbd.2006.06.014. Epub 2006 Aug 22.


Resistance to drug treatment is an important hurdle in the therapy of many diseases, including cancer, infectious diseases and brain disorders such as epilepsy. A phenotype that is referred to as multidrug resistance was first described for chemotherapy-resistant cancer cells that overexpressed the drug efflux transporter P-glycoprotein (P-gp). More recently, overexpression of P-gp has been found in capillary endothelial cells of epileptogenic brain tissue from patients with medically intractable epilepsy. Such regionally restricted P-gp overexpression in the blood-brain barrier is likely to reduce the concentration of antiepileptic drugs at epileptic neurons, which would be a plausible explanation for multidrug resistance in epilepsy. However, a definite proof-of-principle for this hypothesis is lacking. In the present study, we used a rat model of temporal lobe epilepsy that allows selecting drug-resistant and drug-responsive subgroups of epileptic rats by prolonged treatment with the antiepileptic drug phenobarbital at maximum tolerated doses. We have shown recently that drug-resistant rats selected from this model exhibit a marked overexpression of P-gp in the hippocampus and other limbic brain regions. This model is thus ideally suited to prove the multidrug transporter hypothesis of drug resistance. For this purpose, we selected a group of phenobarbital-resistant rats, which was subsequently treated by combinations of phenobarbital with the selective P-gp inhibitor tariquidar. Coadministration of tariquidar (15-20 mg/kg) fully restored the anticonvulsant activity of phenobarbital without altering plasma pharmacokinetics or neurotoxicity of the antiepileptic drug. These data demonstrate that inhibiting P-gp in epileptic rats with proven drug resistance counteracts resistance, providing the first proof-of-principle of the multidrug transporter hypothesis of medically refractory epilepsy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • Animals
  • Anticonvulsants / pharmacokinetics
  • Anticonvulsants / pharmacology*
  • Carrier Proteins / genetics*
  • Drug Resistance, Multiple / genetics*
  • Electrodes, Implanted
  • Electroencephalography / drug effects
  • Epilepsy, Temporal Lobe / genetics*
  • Epilepsy, Temporal Lobe / metabolism*
  • Female
  • Phenobarbital / pharmacokinetics
  • Phenobarbital / pharmacology
  • Quinolines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Seizures / physiopathology
  • Stereotaxic Techniques


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Anticonvulsants
  • Carrier Proteins
  • Quinolines
  • tariquidar
  • Phenobarbital