Sodium valproate is metabolized to 4-en-valproic acid via beta-oxidation in the mitochondria. This metabolite is specifically responsible for which serious adverse effect?

• A Thrombocytopenia due to inhibition of thrombopoietin receptor
• B Spina bifida and neural tube defects through induction of CYP2C9 in folate metabolism
• C Pancreatitis through lipase activation in pancreatic acinar cells
• D Hepatotoxicity due to inhibition of beta-oxidation and CoA sequestration leading to microvesicular steatosis ✓

Explanation

Valproate undergoes extensive hepatic metabolism; one pathway via mitochondrial beta-oxidation produces 4-en-valproic acid (4-en-VPA), a hepatotoxic metabolite. It inhibits mitochondrial beta-oxidation of other fatty acids, depletes CoA (coenzyme A) by sequestration, and impairs the electron transport chain, leading to accumulation of triglycerides and microvesicular steatosis (the hallmark of valproate hepatotoxicity). Children under 2, those on enzyme-inducing drugs, and those with mitochondrial diseases (e.g., Alpers syndrome due to POLG mutations) are at highest risk. Neural tube defects involve HDAC inhibition and folate pathway interference but are a distinct mechanism from the hepatotoxic metabolite.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.