Intravenous phenytoin and phenobarbital: anticonvulsant action, brain content, and plasma binding in rat.

14C-phenytoin or 3H-phenobarbital were given through indwelling jugular catheters to 65 rats. Anticonvulsant activity was tested by the maximal electroshock seizure test and was correlated with brain concentrations of phenytoin or phenobarbital. Free and total plasma drug levels were determined by equilibrium dialysis. The median effective cerebral phenytoin concentration (EC50) was 10.5 microM/kg (95% fiducial limits, 8.2 to 12.4) 3 min after infusion compared with 10.2 microM/kg 30 min after infusion. The EC50 of phenobarbital was 8.2 microM/kg (6.7 to 9.3 microM/kg) 3 min after infusion. Cerebellar concentrations were equivalent to cerebral concentrations for all rats (r = 0.98). Three minutes after infusion, cerebral:plasma free ratio of phenytoin was 3.73 +/- 0.71 (+/- S.D.); the plasma protein bound:free ratio, 3.70 +/- 0.98. For phenobarbital, the cerebral:plasma free ratio was 0.72 +/- 0.10; the plasma protein bound:free ratio, 0.63 +/- 0.12. Since the EC50 values of phenytoin 3 or 30 min after infusion did not differ, onset of anticonvulsant effect clearly occurred as soon as adequate brain concentrations were attained. Phenobarbital was effective 3 min after infusion, and although much higher free plasma levels were necessary, effective brain concentrations were similar to those of phenytoin. Brain content paralleled plasma protein binding, both being high for phenytoin and low for phenobarbital.