Although a series of new antiepileptic drugs (AEDs) have been launched in the last two decades, drug-refractoriness remains a major problem concerning 20-30% of epileptic patients. The fact that most patients with refractory epilepsy are resistant to several AEDs acting via different targets points to an involvement of unspecific mechanisms like changes in local uptake of AEDs in the epileptic focus region. Increased expression of multidrug transporters has been reported in epileptogenic brain tissue from pharmacoresistant patients undergoing epilepsy surgery. However, only limited information exists on the extent to which AEDs are transported by multidrug transporters like P-glycoprotein (PGP). In the present study, the effect of PGP inhibition by verapamil on brain access of the AEDs phenobarbital, lamotrigine, and felbamate was investigated by in vivo microdialysis in rats. Local perfusion of verapamil via the microdialysis probe increased the concentration of the three AEDs in the extracellular fluid of the cerebral cortex in a significant manner. The data indicate that overexpression of PGP in epileptic tissue is likely to limit brain access of the AEDs phenobarbital, lamotrigine, and felbamate, thus favoring the hypothesis that multidrug transporters play a crucial role in the phenomenon of drug-refractory epilepsy.