Valproate metabolism:

Most VPA is glucuronidated (50-80%).

Most of the rest undergoes β-oxidation (up to 40%) in the mitochondria to 2-en-VPA-CoA

A small amount (<10%) undergoes ω-oxidation in the endoplasmic reticulum to 4-en-VPA (hepatotoxin)

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β-oxidation of VPA depletes carnitine by:

1. VPA forms VPA-carnitine, which is is renally excreted
2. VPA-carnitine inhibits the hepatocyte carnitine transporter
3. 2-en-VPA-CoA traps mitochondrial CoA. This decreases production of ATP & N-acetylglutamte

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More on β-oxidation of VPA depleting carnitine:

N-acetylglutamine is an obligatory co-factor for carbamoylphosphate synthase I (CPS1).

CPS1 is the primary enzyme responsible for incorporating ammonia (NH3) into the urea cycle.

CPS1 malfunction causes NH3

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Meanwhile, the ω-oxidation product (4-en-VPA):

1. also (likely) inhibits CPS1 causing NH3
2. is steatogenic (microvesicular, like hypoglycin A)
3. also (likely) directly hepatotoxic itself

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VPA metabolism summary:

β-oxidation in the mitochondria (to 2-en-VPA-CoA) decreases CoA, ATP, and CPS1 co-factors, and is the primary driver of carnitine depletion.

ω-oxidation (to 4-en-VPA) is steatogenic, maybe hepatotoxic, & may also inhibit CPS1 to NH3

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