To review the relevant literature concerning the biochemical mechanism(s) of valproic acid (VPA)-induced hyperammonemia in an attempt to present a unifying pathogenetic hypothesis.
Data Sources
The MEDLINE database (1966–July 2001) was searched for English-language articles and abstracts on VPA-induced hyperammonemia. References cited in relevant primary articles were also reviewed.
Study Selection
More than 150 original and review articles were evaluated, and the most relevant were selected.
Data Extraction
Clinically significant hyperammonemia is a rare adverse effect of VPA therapy. The exact pathogenesis of VPA-induced hyperammonemia remains unclear, but is likely to involve a variety of contributing and possibly overlapping biochemical steps. These include VPA drug concentration, indirect inhibition of ureagenesis by valproyl coenzyme A (CoA), direct suppression of the urea cycle enzymes, depletion of mitochondrial acetyl CoA and decreased production of N-acetylglutamate, depletion of carnitine stores, and increased glutamate dehydrogenase activity.
Conclusions
Hyperammonemic encephalopathy is a rare, but clinically important, adverse effect of VPA therapy. The biochemical basis for this association remains unclear. Awareness of this adverse reaction by healthcare personnel is important in early recognition, treatment, and prevention.
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