Pharmacologic interactions between valproate and other drugs.

Valproate is often administered with other antiepileptic drugs, a practice that can lead to clinically significant pharmacologic interactions. Concomitant administration of such enzyme-inducing antiepileptic drugs as carbamazepine, phenobarbital, primidone, or phenytoin will markedly accelerate the metabolic conversion of valproate, particularly in children. In response to the effects of enzyme induction, valproate dosage may need to be doubled to maintain therapeutic serum levels. Valproate does not appear to induce enzymatic drug metabolism, but rather acts as a metabolic inhibitor. Because of this inhibition, phenobarbital dosage must often be reduced after valproate is added to the therapeutic regimen. Valproate also may markedly increase concentrations of the active epoxide metabolite of carbamazepine. The interaction between phenytoin and valproate results primarily from displacement from plasma proteins. The resulting increase in the free fraction of phenytoin alters the relationship between total phenytoin concentration and the drug's pharmacologic effect. Thus, clinical evidence of toxicity may be present at concentrations usually considered to be in the therapeutic range.