Impact of seizure activity on free extracellular phenytoin concentrations in amygdala-kindled rats

Access of antiepileptic drugs (AEDs) to the epileptic focus region is considered to be influenced by seizure-associated changes in blood-brain barrier (BBB) function and blood flow. Enhanced leakiness of the BBB has been reported as a consequence of seizure activity, and this is controversially discussed to either favor accumulation of AEDs in epileptic tissue or to limit free extracellular concentrations of AEDs due to enhanced protein extravasation. On the other hand, multidrug transporter overexpression has been described following seizure activity, which can limit brain penetration of AEDs in brain regions involved in seizure generation and spread. Aim of the present study was to determine, how these complex alterations at the BBB influence penetration of a standard AED to the site of seizure initiation. Microdialysis experiments were performed in amygdala-kindled rats and in electrode-implanted, non-kindled rats with the microdialysis probe located directly adjacent to the stimulation-recording depth electrode. Penetration of the AED phenytoin to the extracellular fluid in the focus region was investigated at different time points in relation to seizure activity elicited in kindled rats. Integrity of the BBB was determined by Evans blue. Access of phenytoin to the amygdala proved to be comparable in non-kindled, electrode-implanted control rats and in kindled rats 2 h or fourteen days following a single generalized seizure. When a single generalized seizure was elicited 10 min following phenytoin administration, average phenytoin brain dialysate levels were significantly lower (up to 45%) than those of control animals. During a self-sustained status epilepticus, phenytoin access to the site of seizure initiation tended to be lower in the early phase following drug administration, but reached control level 2 h later. The data clearly demonstrate that seizure-induced alterations in BBB integrity and function do not increase extracellular brain levels of phenytoin in affected brain regions, but rather tend to decrease the free concentration of phenytoin in the extracellular compartment.