Is 2‐Propyl‐4‐Pentenoic Acid, a Hepatotoxic Metabolite of Valproate, Responsible for Valproate‐Induced Hyperammonemia?

Abstract

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).

The effect of carnitine supplementation in valproate‐induced hyperammonaemia

“…Hyperammonaemia, as defined by a plasma ammonia concentration of >80pg/dl, was shown by about 35Yn of our patients, which is in agreement with the generally reported high frequency of this disturbance (3,10,16). The present results confirm those studies reporting no relationship between plasma ammonia concentrations and age, time on VPA therapy, VPA dosage and plasma VPA concentration (3,16). Nevertheless.…”

Risk factors for hyperammonemia in pediatric patients with epilepsy

“…Our previous study established that high‐dose VPA therapy, concomitant use of hepatic enzyme inducers, and concomitant use of topiramate (TPM) were risk factors for an increase of the blood ammonia level in adult patients with epilepsy who were treated with VPA (Yamamoto et al., ). There have also been some reports regarding the risk of hyperammonemia in pediatric patients with epilepsy (Coulter & Allen, ; Batshaw & Brusilow, ; Murphy & Marquardt, ; Ohtani et al., ; Haidukewych et al., ; Laub, ; Iinuma et al., ; Thom et al., ; Kondo et al., ; Altunbaşak et al., ; Sharma et al., ). Verrotti et al.…”

“…). There have also been some reports regarding the risk of hyperammonemia in pediatric patients with epilepsy (Coulter & Allen, 1981;Batshaw & Brusilow, 1982;Murphy & Marquardt, 1982;Ohtani et al, 1982;Haidukewych et al, 1985;Laub, 1986;Iinuma et al, 1988;Thom et al, 1991;Kondo et al, 1992;Altunbas ßak et al, 1997;Sharma et al, 2011). Verrotti et al (1999) found that the VPA dose, the duration of treatment, and polytherapy were associated with hyperammonemia.…”

A Case of Infectious Enterocolitis with Hyperammonemia

“…The influence of urease-producing bacteria and renal dysfunction were considered to be the causes of hyperammonemia in this case, but since renal dysfunction alone rarely causes hyperammonemia, the main cause of hyperammonemia was suspected to be infection with urease-producing bacteria. Hyperammonemia may occur due to the side effects of drugs such as valproic acid [10,11], but she was not medicated with any drugs that could cause hyperammonemia.…”