From the FDA Drug Label
Hyperammonemia has been reported in association with valproate therapy and may be present despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy.
The mechanism by which Depakote (valproate) causes hyperammonemia is not explicitly stated in the drug label. However, it is mentioned that patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia, suggesting that valproate may interfere with ammonia metabolism in some way. Key points to consider include:
- Hyperammonemia can occur despite normal liver function tests
- Valproate therapy should be discontinued if ammonia levels are increased
- Underlying urea cycle disorders should be investigated in patients with hyperammonemia 1
From the Research
Depakote (valproate) causes hyperammonemia primarily by inhibiting enzymes in the urea cycle, which is responsible for converting ammonia to urea for excretion, as supported by the most recent study 2. The mechanism of valproate-induced hyperammonemia is complex and multifactorial.
- Valproate inhibits carbamoyl phosphate synthetase I and N-acetylglutamate synthetase, two key enzymes in the urea cycle, leading to impaired ammonia detoxification 2.
- Additionally, valproate increases the production of ammonia in the kidneys by enhancing glutamine uptake and stimulating glutaminase activity, further contributing to hyperammonemia 3.
- Valproate also reduces the availability of carnitine, which is necessary for fatty acid metabolism, leading to secondary carnitine deficiency and impaired mitochondrial function, which compromises ammonia detoxification 4. The risk of hyperammonemia is higher in patients with underlying urea cycle disorders, those on multiple anticonvulsants (particularly topiramate or phenobarbital), and individuals with liver dysfunction, as highlighted in a case report 5.
- Clinicians should monitor ammonia levels in patients on Depakote who develop unexplained lethargy, vomiting, or changes in mental status, and consider L-carnitine supplementation as a potential treatment for valproate-induced hyperammonemia, with typical doses ranging from 50-100 mg/kg/day divided into 2-3 doses, especially in high-risk patients 2. It is essential to note that the risk of hyperammonemia can be increased by synergistic interactions with other medications, such as topiramate, as suggested by a case analysis 6.