Pharmacodynamic interaction between phenytoin and sodium valproate changes seizure thresholds and pattern.
1. In this study we used cortical stimulation to assess the effects of phenytoin (PHT), sodium valproate (VPA), and their interaction on total motor seizure and on the constituent elements of the seizure. 2. PHT (40 mg kg(-1)) was administered as an intravenous bolus infusion to animals receiving either a continuous infusion of VPA or saline. VPA plasma concentration was maintained at levels that produced no detectable anticonvulsant effect. 3. Analysis of ictal components (eyes closure, jerk, gasp, forelimb, clonus, and hindlimb tonus) and their durations revealed both qualitative and quantitative differences in drug effects. 4. The anticonvulsant effect is represented by the increase in the duration of the stimulation required to reach a given seizure threshold. PHT significantly increased the duration of the stimulation and of the motor seizure. This increase was greatly enhanced by VPA. In addition, ictal component analysis revealed that the combination of PHT and VPA causes the reduction of a specific seizure component (JERK). 5. Neither the free fraction of PHT nor the biophase equilibration kinetics changes in the presence of VPA. It is concluded that the synergism may be due to a pharmacodynamic rather than a pharmacokinetic interaction.
Della Paschoa
O E
OE
Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands.
Kruk
M R
MR
Hamstra
R
R
Voskuyl
R A
RA
Danhof
M
M
D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004347:Drug Interactions; D008297:Male; D010672:Phenytoin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000378:metabolism / Q000517:prevention & control*; D014635:Valproic Acid / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000927:Anticonvulsants; D014635:Valproic Acid; D010672:Phenytoin