title: Levetiracetam and felbamate interact both pharmacodynamically and pharmacokinetically: an isobolographic analysis in the mouse maximal electroshock model.
abstract: OBJECTIVE
  Polytherapy with two or more antiepileptic drugs (AEDs) is generally required for approximately 30% of patients with epilepsy, who do not respond satisfactorily to monotherapy. The potential usefulness of AED combinations, producing synergistic anticonvulsant efficacy and minimal adverse effects, is therefore of significant importance. The present study sought to ascertain the potential usefulness of levetiracetam (LEV) and felbamate (FBM) in combination in the mouse maximal electroshock (MES)-induced seizure model.
  
  
  METHODS
  The anticonvulsant interaction profile between LEV and FBM in the mouse MES-induced seizure model was determined using type II isobolographic analysis. Acute adverse effects (motor performance) were ascertained by use of the chimney test. LEV and FBM brain concentrations were measured by HPLC in order to determine any pharmacokinetic contribution to the observed antiseizure effect.
  
  
  RESULTS
  LEV in combination with FBM, at the fixed ratios of 1:2, 1:1, 2:1, and 4:1, were supraadditive, whereas at the fixed ratio of 1:4, additivity was observed in the mouse MES model. Furthermore, none of the investigated combinations altered motor performance in the chimney test. Brain FBM concentrations were unaffected by concomitant LEV administration. In contrast, FBM significantly increased LEV brain concentrations.
  
  
  CONCLUSIONS
  LEV in combination with FBM was associated with pharmacodynamic supraadditivity in the MES test. However, this anticonvulsant supraadditivity was associated with a concurrent increase in brain LEV concentrations indicating a pharmacokinetic contribution to the observed pharmacodynamic interaction between LEV and FBM.
authors.affiliation: Department of Pathophysiology, Medical University of Lublin, Jaczewskiego, Lublin, Poland.
authors.forename: Jarogniew J
authors.initials: JJ
authors.lastname: Luszczki
authors.forename: Marta M
authors.initials: MM
authors.lastname: Andres-Mach
authors.forename: Neville
authors.initials: N
authors.lastname: Ratnaraj
authors.forename: Philip N
authors.initials: PN
authors.lastname: Patsalos
authors.forename: Stanislaw J
authors.initials: SJ
authors.lastname: Czuczwar
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004357:Drug Synergism; D004597:Electroshock; D004827:Epilepsy / Q000378:metabolism / Q000517:prevention & control; D000078328:Felbamate; D006801:Humans; D000077287:Levetiracetam; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D048448:Phenylcarbamates / Q000493:pharmacokinetics* / Q000494:pharmacology*; D010889:Piracetam / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D011409:Propylene Glycols / Q000493:pharmacokinetics* / Q000494:pharmacology*; D012640:Seizures / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D000927:Anticonvulsants; D048448:Phenylcarbamates; D011409:Propylene Glycols; D000077287:Levetiracetam; D000078328:Felbamate; D010889:Piracetam