The Effects of Valproate on Plasma Concentration of Phenytoin in Normal and D-Galactosamine-Treated Rats

The effect of valproate on the plasma concentration of phenytoin was examined in both normal and D-galactosamine-treated rats. In normal rats the total plasma concentration of phenytoin decreased and the plasma concentration of unbound phenytoin increased after the injection of valproate (300 mg/kg). By contrast, in rats showing low binding as a result of d-galactosamine treatment, the total and unbound concentrations of phenytoin in plasma were almost unchanged after the injection of valproate. Possible mechanisms to explain the above results are discussed in this paper on the basis of the results of plasma protein binding and tissue distribution studies. One such possible mechanism was thought to be that decrease in the total plasma concentration of phenytoin after valproate injection in normal rats may have resulted from an increased volume of distribution which is dependent on increase in the unbound fraction of phenytoin in plasma. On the other hand, one possible reason why valproate produced no significant influence on the total and unbound concentrations of phenytoin in plasma in the rats showing low binding may have been an unchanged volume of distribution of phenytoin preceding and following the injection of valproate which would have been dependent on the lack of change in the unbound fraction. The molar ratio of nonesterified fatty acid (NEFA)/albumin of the plasma protein was increased by D-galactosamine treatment. As NEFA is considered to be an important inhibitor of phenytoin binding to rat plasma, it could be speculated that valproate does not act as an inhibitor of phenytoin binding in rat plasma when the NEFA/albumin molar ratio of plasma protein is increased.