Abstracts

Decreased access of antiepileptic drugs to the epileptic focus region due to enhanced multidrug transporter expression at the blood-brain barrier is considered to be one mechanism involved in drug-refractoriness of epilepsy. Investigations in different rodent models of epilepsy have demonstrated induction of multidrug transporter expression in response to seizure activity. Furthermore transporter mediated efflux of phenytoin (PHT) at the blood-brain barrier has been demonstrated for two multidrug transporters. The aim of the present study was to evaluate the impact of overexpression of multidrug transporters and of an acute leakiness of the blood-brain barrier in response to seizures, which has been reported repeatedly, on concentrations of PHT in the epileptic focus region.
Bipolar electrodes and guide cannulae were implanted side by side in the amygdala of female Wistar rats. The animals were kindled by daily constant current electrostimulation. Microdialysis experiments were performed in fully kindled rats. PHT was administered 14 days or 2 hours following a single generalized seizure induced by stimulation via the depth electrode. PHT plasma and amygdala dialysate concentrations were repeatedly analyzed by HPLC. In additional experiments PHT was administered 10 min prior to a generalized seizure, which was elicited during the microdialysis procedure, or during a self-sustained status epilepticus induced by prolonged electrostimulation of 30 min.
The PHT amygdala dialysate : plasma ratio proved to be up to 30% lower in amygdala kindled rats 14 days following a generalized seizure as compared to the data of sham control rats. When PHT was administered 2 hours following the last seizure the ratio was up to 20% lower in the kindled group as compared to the sham group. The differences between both groups proved to be not significant. Induction of a seizure 10 min following phenytoin administration did not change the brain access of PHT in a significant manner. Administration of PHT during status epilepticus resulted in a slightly decreased brain access of PHT, but the data did not differ significantly as compared to the dialysate : plasma ratio in the other experiments.
The present data demonstrated a general trend for lower extracellular PHT levels in the focus region of kindled rats, which could be a consequence of multidrug transporter overexpression induced by seizures. With regard to the interindividual differences that were obvious in this study future experiments should test if subgroups of kindled rats not responding to PHT treatment are characterized by high multidrug transporter expression and low PHT concentration in the epileptic focus. Furthermore the present observations give evidence that the general assumption that seizure activity favors access of antiepileptic drugs to the focus by increasing blood-brain barrier leakiness and increasing local blood flow must be reconsidered.
[Supported by: Deutsche Forschungsgemeinschaft Lo 274/9-2]