title: Pharmacodynamic and pharmacokinetic interaction profiles of levetiracetam in combination with gabapentin, tiagabine and vigabatrin in the mouse pentylenetetrazole-induced seizure model: an isobolographic analysis.
abstract: To characterize the interactions between levetiracetam and the antiepileptic drugs gabapentin, tiagabine, and vigabatrin in suppressing pentylenetetrazole-induced clonic seizures in mice, type II isobolographic analysis was used. Clonic seizures were evoked in Albino Swiss mice by subcutaneous injection of pentylenetetrazole at its CD(97)(98 mg/kg). Adverse-effect profiles with respect to motor performance, long-term memory and skeletal muscular strength were measured along with total brain antiepileptic drug concentrations. The combination of gabapentin with levetiracetam at the fixed-ratios of 2:1, 1:1, 1:2, and 1:4 were supra-additive (synergistic) in terms of seizure suppression whilst the combination at the fixed-ratio of 4:1 was additive. Tiagabine with levetiracetam and vigabatrin with levetiracetam at the fixed-ratios of 1:25, 1:50, 1:100, 1:200, and 1:400 and at 2:1, 3:1, 4:1, 6:1, 8:1, and 16:1 were additive, respectively. No acute adverse effects were observed. Measurement of total brain antiepileptic drug concentrations revealed that levetiracetam in combination with gabapentin at the fixed-ratio of 1:4 significantly elevated (21%) total brain gabapentin concentrations. In contrast, levetiracetam was without affect on tiagabine or vigabatrin concentrations and co-administration with gabapentin, tiagabine or vigabatrin had no effect on levetiracetam brain concentrations, indicating the pharmacodynamic nature of interaction between these antiepileptic drugs in the mouse pentylenetetrazole model. The combination of gabapentin with levetiracetam at the fixed-ratios of 2:1, 1:1, 1:2, and 1:4 appears to be particularly favorable combination exerting supra-additive interaction in suppressing pentylenetetrazole-induced seizures, although there is a pharmacokinetic contribution to the interaction between levetiracetam and gabapentin at the fixed-ratio of 1:4. Levetiracetam in combination with tiagabine and vigabatrin appear to be neutral combinations producing only additivity in the mouse pentylenetetrazole model.
authors.affiliation: Department of Pathophysiology, Medical University of Lublin, Lublin, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Dudra-Jastrzebska
authors.forename: Marta M
authors.initials: MM
authors.lastname: Andres-Mach
authors.forename: Marcin
authors.initials: M
authors.lastname: Sielski
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
authors.forename: Jarogniew J
authors.initials: JJ
authors.lastname: Luszczki
mesh_terms: D000588:Amines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D004195:Disease Models, Animal; D004347:Drug Interactions; D004357:Drug Synergism; D000077206:Gabapentin; D000077287:Levetiracetam; D008297:Male; D051379:Mice; D009557:Nipecotic Acids / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D010433:Pentylenetetrazole; D010889:Piracetam / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D012640:Seizures / Q000517:prevention & control*; D000078308:Tiagabine; D014018:Tissue Distribution / Q000187:drug effects; D020888:Vigabatrin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000588:Amines; D000927:Anticonvulsants; D003509:Cyclohexanecarboxylic Acids; D009557:Nipecotic Acids; D000077287:Levetiracetam; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D020888:Vigabatrin; D010433:Pentylenetetrazole; D000078308:Tiagabine; D010889:Piracetam