The effects of cimetidine chronic treatment on conventional antiepileptic drugs in mice

Purpose the aim of this study was to evaluate the effects of 1-day,7-day and 14-day administrations of cimetidine on the anticonvulsant activity of conventional antiepileptic drugs (aeds; valproate,carbamazepine,phenytoin and phenobarbital) against maximal electroshock (mes)-induced convulsions in mice. material and methods electroconvulsions were evoked in albino swiss mice by a current delivered via ear-clip electrodes. in addition,the effects of cimetidine,aeds alone and their combinations were studied on performance and long-term memory tests. pharmacokinetic changes in plasma and brain concentrations of aeds after cimetidine administration were evaluated with immunofluorescence. results cimetidine (up to 100 mg/kg) after 1-day administration did not affect the electroconvulsive threshold in animals. moreover,in the 14-day treatment,cimetidine administered at a dose of 40 mg/kg did not significantly change the electroconvulsive threshold in the mes-test,cimetidine administered 14-day (at 20 mg/kg) significantly increased the anticonvulsant activity of carbamazepine,staying without effects after a 1-day and 7-day studies. in contrast,both the 7-day and 14-day administrations of cimetidine resulted in significant reductions of protective efficacy of the phenobarbital. only valproate and phenytoin were not affected by cimetidine (20 mg/kg) in all experimental period. cimetidine administered 1-day,did not alter total brain concentrations and free plasma levels of all aeds tested,whilst the 14-day study elevated carbamazepine plasma and brain concentration and reduced phenobarbital brain concentration. cimetidine co-applied with aeds did not impair performance of mice evaluated in the chimney test however,it worsened long-term memory in animals. conclusions based on this preclinical study,a special caution is advised when treating epileptic patients with combinations of phenobarbital or carbamazepine with cimetidine. © 2015 institute of pharmacology,polish academy of sciences.