Abstracts

Pharmacoresistance in epileptic patients may be described by two explanations that are not necessarily mutually exclusive: a pharmacokinetic mechanism and a pharmacodynamic mechanism. Evidence in favor of the pharmacokinetic hypothesis includes the identification of increased levels of drug transporters at the epileptic blood-brain barrier expression of polymorphic variants of MDR1, and suboptimal levels of drug in the CNS of multiple drug resistant patients. The pharmacodynamic hypothesis is based in the assumption that relevant targets for AED action are altered in either expression levels or protein sequence in the brain of drug resistant epileptics. To investigate the relative contribution of each mechanism, concentrations of carbamazepine (CBZ) and phenytoin (PHT) found in drug resistant brain were directly applied to human cortical slices made hyperexcitable and hypersynchronous by a variety of pharmacological manipulations. The results were compared to rodent data obtained in presumably drug respondent animals. All the experiments were done using human neocortical tissue consisting of small portions of the brain areas excised for therapeutical reasons in patients with pharmacoresistant epilepsy. Temporal lobe tissue was taken from the inferior or middle temporal gyrus as part of a standard temporal lobectomy; frontal or parietal lobe samples were chosen from the most epileptogenic areas, as determined by chronic subdural grid or intraoperative electrocorticographic recordings. Standard electrophysiological techniques were used to record epileptiform activity in vitro. When concentrations of CBZ found in multiple drug resistant brain were directly applied to human cortical slices made hyperexcitable and hypersynchronous by Mg-free aCSF, the frequency of bursts was not significantly affected. The overall excitability was reduced by only 40%. Similar results were obtained for PHT. At higher AED concentrations a dose dependent decrease of bursting frequency and amplitude was observed. Virtually identical findings were obtained in mouse or rat neocortical slices. All human slices responded to AED in vitro regardless of the means used to induced epileptiform activity (spontaneous burtsing, high K, blockade of GABA). Our results strongly support the notion that multiple drug resistance in epileptic patients is not a consequence of intrinsic, pharmacodynamic changes but rather due to insufficient drug penetration in the CNS environment of refractory epileptic patients. This can be accounted for by the overexpression of multiple drug resistance transporters at the blood-brain barrier previously characterized in numerous studies. Our conclusions are based on the fact that rodent brain and human multiple resistant cortex responded identically to AED in vitro. (Supported by HL51614, NS43284, NS38195 and NS46513 to DJ.)