Abstracts

Rationale: Overexpression of multidrug transporters (MDTs) could play a major role in pharmacoresistance by transporting epileptic drugs (AEDs), resulting in insufficient brain concentrations. A recent study in control rats suggests that levetiracetam (LEV), a relatively novel AED, is not a substrate for MDTs. Since rats with chronic epilepsy have increased MDT expression we studied in these rats whether LEV: 1) enters the brain adequately 2) effectively controls seizure activity.Methods: Chronic epileptic rats were treated repeatedly with different LEV dosages with a 2 week interval either via continuous infusion using osmotic minipumps or via bolus injections. The anticonvulsive effects were determined by video-EEG monitoring and the concentration of LEV was measured in plasma and brain homogenates using gas chromatography.Results: LEV adequately entered the epileptic brain and dose-dependently suppressed spontaneous seizures in chronic epileptic rats for 3-4 days. Hereafter, seizure frequency increased, while LEV plasma levels did not change. LEV did not affect seizure duration. However, seizure severity was permanently reduced. Tolerance to LEV was not permanent, since all rats initially responded to LEV after the withdrawal period. Co-administration of phenytoin increased LEV plasma levels considerably, but could not prevent the development of tolerance. Conclusions: Although adequate serum and brain levels of LEV were maintained, chronic LEV treatment provided only temporary seizure control, suggesting pharmacological tolerance to LEV. Repeated LEV administration indicated that the loss of efficacy was not permanent. Whether intermittent administration might be a useful approach for patients who develop tolerance to LEV needs to be investigated.