LIMBIC EPILEPTOGENESIS ALTERS THE ANTICONVULSANT EFFICACY OF PHENYTOIN IN SPRAGUE-DAWLEY RATS

Studies on the anticonvulsant efficacy of the major antiepileptic drug phenytoin in kindled rats have often reported inconsistent effects. I t has been proposed that technical and genetic factors or poor and var iable absorption of phenytoin after i.p. or oral administration may be involved in the lack of consistent anticonvulsant activity of phenyto in in this model of temporal lobe epilepsy. We examined if kindling it self changes the anticonvulsant efficacy of phenytoin by testing this drug before and after amygdala kindling in male and female Sprague-Daw ley rats. To exclude the possible bias of poor and variable absorption , blood was sampled in all experiments for drug analysis in plasma. Th e threshold for induction of focal seizures (afterdischarge threshold; ADT) was used for determining phenytoin's anticonvulsant activity. Be fore kindling, phenytoin, 75 mg/kg i.p., markedly increased ADT in bot h genders, although the effect was more pronounced in males. Following kindling, the anticonvulsant activity obtained with phenytoin, 75 mg/ kg, before kindling was totally lost, and female rats even exhibited a proconvulsant effect upon administration of this dose, indicating tha t kindling had dramatically altered the anticonvulsant efficacy of phe nytoin. Plasma levels of phenytoin were comparable before and after ki ndling, and were within or near to the 'therapeutic range' known from epileptic patients. When the dose of phenytoin was reduced to 50 or 25 mg/kg i.p., significant anticonvulsant effects on ADT were obtained. When phenytoin, 50 mg/kg, was administered i.p. or i.v. in the same gr oup of fully kindled rats, both anticonvulsant activity and plasma dru g levels were comparable with both routes, indicating that the i.p. ro ute is suited for such studies. The data indicate that kindling alters the dose-response of phenytoin in that a high anticonvulsant dose bec omes ineffective or proconvulsant after kindling, possibly by an incre ased sensitivity of the kindled brain to proconvulsant effects of phen ytoin which normally only occur at much higher doses. If similar alter ations evolve in humans during development of chronic epilepsy, this m ay be involved in the mechanisms leading to intractability of temporal lobe epilepsy. (C) 1998 Elsevier Science B.V. All rights reserved.