To investigate the association between
valproate metabolism (VPA) and VPA-induced
hyperammonemia together with the contribution of VPA hepatotoxicity risk factors such as young age,
polypharmacy, and high serum VPA levels to VPA-induced
hyperammonemia, plasma
ammonia (NH3) levels, serum levels of VPA and its metabolites, and biochemical parameters were determined in 98 patients treated with VPA (53 monopharmacy cases and 45
polypharmacy cases). In monopharmacy patients, plasma NH3 levels did not depend on age, VPA dosage or serum levels. Serum level of
2-propyl-4-pentenoic acid (4-en) showed a negative correlation with plasma NH3 level in the monopharmacy group. In
polypharmacy patients, plasma NH3 levels, serum
glutamic pyruvic transaminase, and
gamma-glutamyl-transpeptidase were significantly higher, while level/dose VPA ratio, 2-en-VPA serum level, and
bilirubin were significantly lower than those in monopharmacy patients. These results suggest that young age and relatively high VPA serum levels within the therapeutic range were unlikely to be risk factors for common
hyperammonemia associated with VPA
therapy and that 4-en was not causally related to this adverse effect. The decreased serum level of 2-en-VPA in
polypharmacy patients may be a reflection of a certain
mitochondrial dysfunction, which might be a mechanism of the increased NH3 levels. The changes in biochemical parameters in
polypharmacy patients were considered results of the
enzyme-inducing activity of coadministered
antiepileptic drugs (AEDs).