Valproic acid has excellent bioavailability and is absorbed through the intestine with no site specificity. The rate of absorption depends on the dosage form. Absorption is faster from the syrup and the gelatin capsule (Depakene). The enteric coated formulation (Depakote) was developed to minimize GI irritation. The coating does not dissolve in the acid medium of the stomach, resulting in delayed absorption with trough levels occurring 4 to 6 hours after dose administration. A controlled-release form (Depakote ER) has been introduced for once-a-day dosing.

Valproic acid is highly (>90%) bound to albumin, but the bound percentage decreases as the concentration increases:

Total concentration Unbound concentration
< 75 mcg/mL 7–9%
About 100 mcg/mL 15%
> 150 mcg/mL 30%

The changes in free fraction result in a change in clearance.

Valproic acid is metabolized by a variety of conjugation and oxidative processes and has multiple metabolites. These metabolites may contribute to both its efficacy and toxicity. Two observations support the contribution of the metabolites to the pharmacologic effects:

  • The pharmacologic effects of valproic acid do not correlate well with the steady-state concentrations of the parent drug.
  • The time course of the pharmacologic effects differs from the pharmacokinetics of the parent drug. That is, the full effects of the drug are not seen until some time after steady-state is achieved and persist for some time after the drug is discontinued.

Some authors have argued that some of the metabolites, though active, may not contribute much to the efficacy of valproic acid because they are present only in low concentrations in plasma and brain. The metabolites of valproic acid also may contribute to the rare, but potentially fatal, hepatotoxicity.26

Valproic acid is a low-extraction drug and its clearance is independent of hepatic blood flow.26-27

Effect of liver disease

The protein binding of valproic acid is decreased in alcoholic cirrhosis and viral hepatitis. The elimination half-life is increased but there is no change in total clearance because clearance of the unbound drug is reduced. The result is an increase in unbound drug with no change in the total drug concentration.28

Liver disease alters the profile of valproic acid metabolites but it is not possible to distinguish between benign and life-threatening hepatic adverse reactions based on the profile of the valproic acid metabolites.29 Valproic acid may cause hepatotoxicity, especially in young children with polytherapy or inborn errors of metabolism. Two retrospective reviews demonstrated that the risks of fatal hepatotoxicity associated with valproic acid are highest in children less than 2 years of age who are taking multiple medications:

Patient age, therapy Risk of fatal hepatoxicity
<2 yr, polytherapy 1 in 500
<2 yr, monotherapy 1 in 7000
>2 yr, polytherapy 1 in 12,000
>2 yr, monotherapy 1 in 45,000

In these reports, no patient over age 10 developed fatal hepatotoxicity with valproic acid, but case reports have associated valproic acid with fatal hepatotoxicity in adults. The hepatotoxicity may be the result of a metabolite that is normally not present or present in low concentrations. This is suggested by the fact that the children receiving polytherapy had severe epilepsy associated with mental retardation, neurologic deficits, congenital anomalies, and other developmental delays. These factors, as well as the comedication, may alter the metabolism of valproic acid.26,29 Animal studies indicate that the mechanism by which valproic acid induces hepatotoxicity is different from its mechanism for antiepileptic activity.

The use of L-carnitine supplementation in the treatment and prophylaxis of valproic-acid–induced liver disease remains controversial. A recent consensus panel recommended L-carnitine supplementation for various groups:

  • patients with certain secondary carnitine-deficiency syndromes
  • patients with symptomatic valproate-associated hyperammonemia
  • patients with multiple risk factors for valproic-acid toxicity or renal associated syndrome
  • infants and young children taking valproic acid 
  • patients with epilepsy using the ketogenic diet who have hypocarnitinemia
  • patients on dialysis
  • premature infants receiving total parenteral nutrition

Effect of GI disease

Changes in gastric pH could change the dissolution of the enteric coating of valproic acid. Since the absorption of valproic acid is not site-specific, it is difficult to predict the effect of GI disease.

Adapted from: Garnett WR. Gastrointestinal and hepatic disease. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;63-74. 
With permission from Elsevier ( 

Reviewed By: 
Steven C. Schachter, MD
Monday, March 1, 2004