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Clinical Pharmacokinetics of Valproic Acid

Clinical Pharmacokinetics volume 5, pages 67–83 (1980)Cite this article

Summary

Valproic acid is rapidly absorbed from the gastrointestinal tract, peak concentrations being attained 1 to 2 hours after administration of the conventional tablet, but later with the enteric-coated tablets. The bioavailability of valproic acid is complete and independent of the preparation used. The apparent volume of distribution is relatively small (0.1 to 0.4 L/kg), due to high plasma protein binding. Protein binding is decreased in patients with renal insufficiency, in patients with chronic liver disease, and possibly in the presence of other displacing agents.

The total plasma clearance of valproic acid is in the range of 5 to 10ml/min. Plasma elimination half-life is between 10 and 16 hours, and does not change after continued treatment with valproic acid alone. In combination therapy with other antiepileptic drugs, the half- life can be as short as 6 to 8 hours due to liver enzyme induction. Renal excretion of unchanged valproic acid accounts for only 1 to 3% of the total dose. Valproic acid is present in cerebrospinal fluid in concentrations equal to the unbound drug in plasma (around 10% of the total concentration). Valproic acid concentration in saliva is less than and unrelated to the free drug concentration in plasma. The drug is excreted into breast milk and evidence suggests that it also crosses the placenta.

Four independent metabolic pathways — glucuronidation, β-oxidation and ω-oxidation (ω1, and ω2) have been demonstrated in man. Analytical difficulties caused by the similarity of the metabolites with many normal endogenous compounds and by chemical lability of several metabolites impede the isolation, identification and especially the quantification of valproic acid metabolites. Quantitative aspects of metabolism are essential for the understanding of drug effects in patients. The main metabolite 3-oxo-valproic acid shows comparable pharmacological activity to valproic acid itself in mice; unsaturated metabolites also show some activity.

In young infants under 2 months of age valproic acid elimination half-life can be 60 hours, but in older children, plasma elimination appears to be identical to the adult situation. Valproic acid elimination is impaired in acute viral hepatitis and in liver cirrhosis. No information is available on valproic acid kinetics in renal insufficiency.

Phenobarbitone plasma concentrations rise under combination therapy with valproic acid, because phenobarbitone elimination is impaired. Valproic acid lowers total plasma concentrations of phenytoin by displacing it from its plasma albumin binding site, but free phenytoin concentrations remain unchanged and phenytoin doses need not be modified. Valproic acid elimination is enhanced in the presence of inducing drugs like phenobarbitone, primidone, phenytoin and carbamazepine.

The valproic acid dose-plasma concentration relationship is curvilinear, since valproic acid protein binding decreases with higher concentrations. Therefore, the increase in the plasma concentration is smaller than expected from the dose increase. The lower value of the therapeutic plasma concentration range of valproic acid is around 50μg/ml. Because of low clinical toxicity the upper value of the therapeutic range has yet to be determined.

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  1. Department of Medicine, University of Bonn, 5300, Bonn-Venusberg, Federal Republic of Germany

    Roland Gugler & Gerd E. von Unruh

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Gugler, R., von Unruh, G.E. Clinical Pharmacokinetics of Valproic Acid. Clin Pharmacokinet 5, 67–83 (1980). https://doi.org/10.2165/00003088-198005010-00002

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Keywords

  • Valproic Acid
  • Clinical Pharmacokinetic
  • Phenobarbitone
  • Epileptic Patient
  • Acute Viral Hepatitis