Anticonvulsant activity of phenobarbital and phenytoin in combination

The anticonvulsant properties of phenobarbital and phenytoin given individually or in various combinations were determined by the maximal electroshock seizure test in rats 2 hours after subcutaneous administration. Drug concentrations in brain and plasma obtained immediately after maximal electroshock seizure were measured by gas-liquid chromatography. Total brain anticonvulsant drug concentrations required to abolish the hindlimb extensor component of maximal electroshock seizure were similar when these drugs were employed singly or in combinations. The median effective brain concentrations (EC50) were: phenobarbital, 12.2 micronmol/kg; phenytoin 12.3 micronmol/kg; and phenobarbital plus phenytoin, 14.8 micronmol/kg. Brain/plasma concentration ratios of these drugs were not affected by concomitant administration of the other agent: phenobarbital alone, 0.73; phenobarbital in the presence of phenytoin 0.77; phenytoin, 1.21; and phenytoin in the presence of phenobarbital, 1.22. Brain and plasma concentrations of phenytoin relative to the dose employed were significantly higher (P less than .001) when phenobarbital was administered concurrently than when phenytoin was given alone. This resulted in an apparent potentiation of anticonvulsant activity at 2 hours when these drugs were administered simultaneously. The anticonvulsant activity of the two combinations could be accounted for by the sum of the concentrations of the individual drugs in brain.