Isobolographic and behavioral characterizations of interactions between vigabatrin and gabapentin in two experimental models of epilepsy.
The aim of this study was to characterize the pharmacodynamic, pharmacokinetic and adverse-effect profiles of vigabatrin and gabapentin. Isobolographic analysis was used in two mouse experimental models of epilepsy: the maximal electroshock seizure threshold test and pentylenetetrazole-induced seizures. In the maximal electroshock seizure threshold test, electroconvulsions were produced by a current with various intensities whilst in the pentylenetetrazole test a CD(97) dose (100 mg/kg) was used. Potential adverse-effect profiles of interactions of vigabatrin with gabapentin at three fixed-ratios of 1:3, 1:1 and 3:1 from both seizure tests were evaluated in the chimney (motor performance) and grip-strength (skeletal muscular strength) tests. Vigabatrin and gabapentin total brain concentrations were determined with high performance liquid chromatography. Vigabatrin and gabapentin administered singly increased the electroconvulsive threshold (TID(20) - 226.2 and 70.0 mg/kg, respectively). With isobolography, the combination of vigabatrin with gabapentin at the fixed-ratio of 1:3 exerted supra-additive (synergistic) interactions whilst at 1:1 and 3:1 additivity occurred. Similarly, vigabatrin and gabapentin administered singly suppressed the pentylenetetrazole-induced seizures (ED(50) values - 622.5 and 201.1 mg/kg, respectively). Isobolography revealed that vigabatrin with gabapentin in combination at the fixed-ratio of 1:1 produced supra-additive (synergistic) interaction whilst at 1:3 and 3:1 additivity occurred. In combination neither motor coordination nor skeletal muscular strength was affected. Total vigabatrin and gabapentin brain concentrations revealed that neither drug affected the pharmacokinetics of the other. Vigabatrin and gabapentin have a favorable pharmacodynamic interaction in animal seizure models in the absence of acute adverse effects or concurrent pharmacokinetic changes.
Luszczki
Jarogniew J
JJ
Department of Pathophysiology, Medical University, Lublin, Poland. jarogniew.luszcki@am.lublin.pl
Ratnaraj
Neville
N
Patsalos
Philip N
PN
Czuczwar
Stanislaw J
SJ
D000588:Amines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation; D000077206:Gabapentin; D008297:Male; D051379:Mice; D053580:Muscle Strength / Q000187:drug effects; D010433:Pentylenetetrazole; D011597:Psychomotor Performance / Q000187:drug effects; D012640:Seizures / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D020888:Vigabatrin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*
D000588:Amines; D000927:Anticonvulsants; D003509:Cyclohexanecarboxylic Acids; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D020888:Vigabatrin; D010433:Pentylenetetrazole