What valproic acid metabolites are responsible for its hepatotoxic and neurotoxic effects?
Valproic acid (VPA) is metabolized in the liver via 3 different pathways – glucuronidation, beta oxidation in the mitochondria, and cytosolic omega (ω and ω1) oxidation. Many metabolites are generated; however, 2-propyl-4-pentenoic acid (4-en-VPA) and 2-propyl-2-pentenoic acid (2-en-VPA) are primarily responsible for the hepatotoxic and neurotoxic effects, respectively. Notably, the long half-life of 2-en-VPA can contribute to the delayed onset of cerebral edema, which can be seen with severe VPA toxicity.
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Contributed by: Cedric White, PharmD (Cedric.White@bmc.org) with oversight from Natalija Farrell, PharmD, BCPS, DABAT (Natalija.Farrell@bmc.org)