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Chapter 36. Valproate

Charles L. Bowden, M.D.
DOI: 10.1176/appi.books.9781585623860.431823

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Valproic acid was first synthesized by Burton in the United States in 1882 and subsequently was used as an organic solvent. The drug's antiepileptic properties were discovered serendipitously by Meunier in 1963 in France. Meunier used valproic acid as a vehicle for other compounds that were being screened for antiepileptic activity. He found that compounds that did not have antiepileptic properties when administered alone inhibited seizure activity when dissolved in valproic acid and concluded that the antiepileptic activity was due to the solvent, valproic acid, rather than to the test drugs (Bowden and McElroy 1995; Fariello and Smith 1989; Meunier et al. 1975).

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FIGURE 36–1. Chemical structure of valproic acid (2-propyl-pentanoic acid).

FIGURE 36–2. Mean plasma valproate concentrations with different formulations.aData derived from different studies after 500-mg doses.DR = delayed-release; ER = extended-release.Source. Abbott Laboratories, data on file.

FIGURE 36–3. Total valproate (VPA) concentrations.As the total concentration of VPA increases, protein-binding sites become saturated, and the percentage of unbound to bound VPA increases.Source. Reprinted from Wilder BJ: "Pharmacokinetics of Valproate and Carbamazepine." Journal of Clinical Psychopharmacology 12 (1, suppl):64S–68S, 1992. Used with permission.

FIGURE 36–4. Two pathways for metabolism of valproate (VPA).VPA is metabolized within the mitochondria by the -oxidative pathway, which metabolizes medium- and long-chain fatty acids. This is the major metabolic pathway used in patients taking VPA as monotherapy. VPA is also metabolized by the microsomal cytochrome P450 pathway, which occurs outside the mitochondria; metabolism via this pathway is increased when VPA is administered in combination with enzyme-inducing drugs (e.g., carbamazepine). 3 OH-VPA = 3-hydroxyvalproate; 3-OXO-VPA = 3-oxo-valproate; 2 VPA = 2-en-valproate metabolite; 4 VPA = 4-en-valproate metabolite; 2,4 VPA = 2,4-en-valproate metabolite; t½ = half-life.Source. Reprinted from Wilder BJ: "Pharmacokinetics of Valproate and Carbamazepine." Journal of Clinical Psychopharmacology 12 (1, suppl):64S–68S, 1992. Used with permission.

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