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.