Mechanism of valproate-phenobarbital interaction in epileptic patients

Valproate effects on phenobarbital biodisposition were examined in a search for the mechanisms of the valproate-induced elevation of plasma phenobarbital during antiepileptic therapy. The study involved patients who were treated with phenobarbital alone and phenobarbital plus valproate. Several kinetic parameters were determined after a pulse dose of stable isotope-labeled phenobarbital, with plasma phenobarbital levels at a steady state. Plasma elimination of labeled phenobarbital was studied by selected ion monitoring. The addition of valproate to the phenobarbital regimen resulted in elevation of plasma phenobarbital and increase in urinary output of unchanged phenobarbital. There was no effect on urinary pH. The rise in plasma phenobarbital was paralleled by lengthening of phenobarbital elimination half-life while the decrease of plasma phenobarbital clearance paralleled the decrease in phenobarbital elimination rate constant. These findings suggest that inhibition of phenobarbital metabolism by valproate is the mechanism for this clinically important drug-drug interaction.