title: Mexiletine and its Interactions with Classical Antiepileptic Drugs: An Isobolographic Analysis.
abstract: Using the mouse maximal electroshock test, the reference model of tonic-clonic seizures, the aim of the present study was to determine the type of interaction between mexiletine (a class IB antiarrhythmic drug) and classical antiepileptics: valproate, carbamazepine, phenytoin, and phenobarbital. Isobolographic analysis of obtained data indicated antagonistic interactions between mexiletine and valproate (for fixed ratio combinations of 1:1 and 3:1). Additivity was observed between mexiletine and valproate applied in proportion of 1:3 as well as between mexiletine and remaining antiepileptics for the fixed ratios of 1:3, 1:1, and 3:1. Neither motor performance nor long-term memory were impaired by mexiletine or antiepileptic drugs regardless of whether they were administered singly or in combination. Mexiletine did not significantly affected brain concentrations of carbamazepine, phenobarbital or phenytoin. In contrast, the antiarrhythmic drug decreased by 23 % the brain level of valproate. This could be, at least partially, the reason of antagonistic interaction between the two drugs. In conclusion, the observed additivity suggests that mexiletine can be safely applied in epileptic patients treated with carbamazepine, phenytoin or phenobarbital. Because of undesirable pharmacodynamics and pharmacokinetic interactions with valproate, mexiletine should not be used in such combinations.
authors.affiliation: Independent Unit of Experimental Neuropathophysiology, Department of Pathophysiology, Medical University, Lublin, Poland. kinga.borowicz@umlub.pl.
authors.forename: Kinga K
authors.initials: KK
authors.lastname: Borowicz-Reutt
authors.affiliation: Independent Unit of Experimental Neuropathophysiology, Department of Pathophysiology, Medical University, Lublin, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Banach
authors.affiliation: Independent Unit of Experimental Neuropathophysiology, Department of Pathophysiology, Medical University, Lublin, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Piskorska
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects* / Q000493:pharmacokinetics; D001362:Avoidance Learning / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D002220:Carbamazepine / Q000009:adverse effects / Q000493:pharmacokinetics; D004347:Drug Interactions; D004597:Electroshock; D008297:Male; D057567:Memory, Long-Term / Q000187:drug effects; D008801:Mexiletine / Q000009:adverse effects* / Q000493:pharmacokinetics; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010634:Phenobarbital / Q000009:adverse effects / Q000493:pharmacokinetics; D010672:Phenytoin / Q000009:adverse effects / Q000493:pharmacokinetics; D012640:Seizures / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D014018:Tissue Distribution; D014635:Valproic Acid / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000927:Anticonvulsants; D008801:Mexiletine; D002220:Carbamazepine; D014635:Valproic Acid; D010672:Phenytoin; D010634:Phenobarbital
keywords: Antiepileptic drugs; Drug interactions; Isobolographic analysis; Maximal electroshock; Mexiletine