title: The effects of cimetidine chronic treatment on conventional antiepileptic drugs in mice.
abstract: OBJECTIVE
  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.
  
  
  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 100mg/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 40mg/kg did not significantly change the electroconvulsive threshold in the MES-test, cimetidine administered 14-day (at 20mg/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 (20mg/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.
authors.affiliation: Department of Experimental and Clinical Pharmacology, Medical University, Lublin, Poland. Electronic address: mariusz.swiader@am.lublin.pl.
authors.forename: Mariusz J
authors.initials: MJ
authors.lastname: Świąder
authors.affiliation: Department of Experimental and Clinical Pharmacology, Medical University, Lublin, Poland.
authors.forename: Bartłomiej
authors.initials: B
authors.lastname: Barczyński
authors.affiliation: Department of Experimental and Clinical Pharmacology, Medical University, Lublin, Poland.
authors.forename: Michał
authors.initials: M
authors.lastname: Tomaszewski
authors.affiliation: Department of Applied Pharmacy, The Medical University of Lublin, Lublin, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Świąder
authors.affiliation: Department of Pathophysiology, Medical University of Lublin, Lublin, Poland; Department of Physiopathology, Institute of Agricultural Medicine, Lublin, Poland.
authors.forename: Stanisław J
authors.initials: SJ
authors.lastname: Czuczwar
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002220:Carbamazepine / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D002927:Cimetidine / Q000494:pharmacology*; D004347:Drug Interactions; D004597:Electroshock / Q000379:methods; D008297:Male; D057567:Memory, Long-Term / Q000187:drug effects; D051379:Mice; D010634:Phenobarbital / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D010672:Phenytoin / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D012640:Seizures / Q000188:drug therapy* / Q000378:metabolism; D014635:Valproic Acid / Q000097:blood / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000927:Anticonvulsants; D002220:Carbamazepine; D014635:Valproic Acid; D010672:Phenytoin; D002927:Cimetidine; D010634:Phenobarbital
keywords: Antiepileptic drugs; Cimetidine; Drug interactions; Electroshock maximal; Seizures