Valproate (VPA) Metabolites in Various Clinical Conditions of Probable VPA‐Associated Hepatotoxicity

Abstract

Of a cohort of 470 epileptic patients in whom valproate (VPA) serum metabolites had been measured, 170 subjects without symptoms or signs of hepatic side effects were chosen as a reference group to establish the usual metabolic pattern. A wide interindividual variation of VPA metabolite concentrations was noted. Infants receiving VPA monotherapy and comedication with other antiepileptic drugs (AEDs) showed lower concentrations of the potential hepatotoxin 4-ene-VPA than did older children. In 11 patients with early symptoms and signs of possible fatal VPA-associated hepatotoxicity, the following spectrum of benign clinical conditions was observed: unusually severe side effect during initiation of VPA therapy (1 patient), high VPA dosage (2 patients), reversible impairment of coagulation with bleeding manifestations in association with a slight increase in transaminase levels (1 child), and reversible liver dysfunction associated with febrile illness (7 patients). Reversible or irreversible fulminant liver failure had occurred in 5 children. Three of the 4 children with a fatal outcome had massive lactic acidosis. In all patients with probable VPA-associated hepatotoxicity, some aspects of VPA metabolism differed distinctly from that of the reference group, but the inter-individual profile of metabolites varied considerably, even in the subgroup of 4 children who died. Impairment of VPA beta-oxidation and increase of metabolites of alternative metabolic pathways (omega- and omega 1-hydroxylation, dehydrogenation reactions) were the most frequent findings. Increased values of 2-n-propyl-4-pentenoic acid metabolite of VPA (4-ene-VPA), could be detected only in 1 of the 5 patients with fulminant liver failure and in one other child with a slight hepatic dysfunction, indicating that this VPA metabolite is not the decisive hepatotoxin or indicator of hepatotoxicity. Because we cannot distinguish between benign and life-threatening hepatic adverse reactions on the basis of VPA metabolites, all identified changes are considered secondary to an as-yet-unknown primary metabolic event. The most toxic compound could be VPA itself, which may unmask an inborn or an acquired metabolic defect in the processing of fatty acids.

Incidence of Death in Patients with Intractable Epilepsy During Nitrazepam Treatment

“…Of the latter, the most common concomitant AEDs were only VPA in four children (6,8,9,13), and CBZ plus VPA in two patients (4 and 5). Other AEDs in the remaining six patients are listed in Table 1.…”

“…VPA is associated with fatal hepatotoxicity (9) and pancreatitis (10). CBZ has been associated with cardiac conduction disturbance (15).…”

“…At the time of death, none of our patients had unusually high concentrations of these two or other AEDs. In the NZP group, six patients (4, 5,6,8,9,13) were taking VPA. None of these children had abnormal blood tests associated with VPA or serious side effects.…”

Valproic acid poisoning: An evidence-based consensus guideline for out-of-hospital management

“…The hyperammonemia appears to be primarily related to depletion of carnitine stores in the mitochondria resulting in interruption of the urea cycle and accumulation of ammonia, although other mechanisms might be involved (17). Depletion of carnitine also shifts the metabolism of valproic acid to a pathway that results in accumulation of a 4-en-valproate metabolite that is thought to be associated with hepatotoxicity but is probably not the definitive hepatotoxin (21). Hepatotoxicity is most commonly seen with therapeutic use of the drug but can also occur following a massive overdose.…”

Evidence for a Trigger Function of Valproic Acid in Xenobiotic‐Induced Hepatotoxicity

“…Different hepatotoxic mechanisms of valproic acid are discussed at present. For instance, unsaturated reactive metabolites of valproic acid have been supposed to be the decisive hepatotoxin, but metabolic patterns in clinically inconspicuous patients and in patients with probable valproic acid-associated hepatotoxicity were similar with respect to formation of potentially harmful metabolites (Siemes et al 1993). This finding does not support the hypothesis of a toxic metabolite of valproic acid.…”