title: A comparison of extracellular levels of phenytoin in amygdala and hippocampus of kindled and non-kindled rats.
abstract: Temporal lobe epilepsy is often refractory to antiepileptic drugs (AEDs). Accordingly, amygdala-kindled rats, a widely used model of temporal lobe epilepsy, have previously been found to be less responsive to AED treatment than non-kindled rats. In view of recent findings of over-expression of multidrug transporters in the blood-brain barrier of patients with pharmacoresistant epilepsy, one explanation for the finding of difficult-to-treat seizures in kindled rats would be a reduced penetration of AEDs into epileptogenic brain tissue. For evaluation of this possibility, we used brain microdialysis in order to compare extracellular levels of the AED phenytoin in amygdala and hippocampus of conscious, unrestrained amygdala-kindled and non-kindled rats. Consistent with the lower anticonvulsant efficacy of phenytoin in kindled rats, average phenytoin levels in dialysates of kindled rats were lower (up to 30%) than in non-kindled controls, but the differences were not statistically significant. This indicates that either the relatively large interindividual variation in dialysate levels of phenytoin masks functionally significant differences in individual kindled rats or that alterations in brain drug penetration are not involved in the lowered response of kindled rats to AEDs.
authors.affiliation: Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
authors.forename: Heidrun
authors.initials: H
authors.lastname: Potschka
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Löscher
mesh_terms: D000679:Amygdala / Q000378:metabolism*; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics*; D005110:Extracellular Space / Q000378:metabolism*; D005260:Female; D006624:Hippocampus / Q000378:metabolism*; D007696:Kindling, Neurologic / Q000502:physiology*; D017551:Microdialysis; D010672:Phenytoin / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values
chemical_list: D000927:Anticonvulsants; D010672:Phenytoin