Pharmacokinetics, drug interactions, and tolerability of valproate

Valproate is a branched-chain carboxylic acid with an extensive history of use as an antiepileptic drug. In recent years, multiple uses for valproate have been found in psychiatry. As divalproex sodium, it is currently approved for the treatment of manic episodes associated with bipolar disorder and for migraine headache prophylaxis. Accumulating evidence suggests it may also be beneficial in several anxiety disorders. Valproate's pharmacokinetic profile has been extensively studied, mostly within the context of treatment of epilepsy. This review summarizes valproate's pharmacokinetics, drug interactions, and tolerability as an aid to promote individualized pharmacotherapy. Valproate is characterized by dose-limited absorption, nonlinear plasma protein binding, and multiple metabolic pathways of elimination. Pharmacokinetic drug interactions involving valproate result from its susceptibility to the effects of both enzyme induction and inhibition, along with an ability for weak to moderate inhibition of the metabolic elimination of other drugs. Valproate has an extensive record of use across the lifespan and a good record of tolerability. Some precautions are warranted in its use, but valproate is generally safe whether administered alone or in combination with other therapies.