Metabolite profiles in patients on high-dose valproate monotherapy

doi:10.1016/0920-1211(96)00019-8

Epilepsy Research

Volume 25, Issue 2, October 1996, Pages 107-112

https://doi.org/10.1016/0920-1211(96)00019-8 Get rights and content

Abstract

To investigate the mechanism of valproate (VPA)-induced hepatotoxicity, we measured the serum and urine metabolites of VPA in high-dose VPA monotherapy by GC/MS/SIM and discussed the relationship between liver function and β-oxidation, ω-, (ω−1)-oxidation metabolites and 4-en-VPA. In high-dose VPA monotherapy, the concentrations of β-oxidation metabolites were not increased except for 2-en-VPA, but the concentrations of {ω+(ω−1)}-oxidation metabolites and 4-en-VPA were increased about 4–5 times compared to those of standard-dose VPA monotherapy. Serum GOT was not significantly correlated to 4-en-VPA and the ratio of β-oxidation/{ω+(ω−1)} oxidation metabolites of VPA in serum. In high-dose VPA monotherapy, it is speculated that the β-oxidation of VPA in the mitochondria reached the saturation point. However, instead of the β-oxidation, the {ω+(ω−1)}-oxidation in microsomes was increased. We could not find significant relationship between the formation of toxic metabolites of VPA and liver dysfunction. Our data in VPA monotherapy suggest that the mechanisms of VPA-induced fatal hepatotoxicity cannot be explained by decreased β-oxidation, increased ω-oxidation and increased 4-en-VPA level.

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Population pharmacokinetic modelling of valproic acid and its selected metabolites in acute VPA poisoning
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Citation Excerpt :
The results are in agreement with our previous findings [5] based on Apple coefficients [27]. Sugimoto et al. [28] investigated metabolite profiles in children at high, yet therapeutic, doses and found that 4VPA concentrations increased proportionally to according to the VPA dose, while β-oxidation metabolites did not increase. Again, these results are in agreement with our conclusions.
Valproic acid (VPA) is a first-line antiepileptic drug. It is used in the treatment of many different types of partial and generalized epileptic seizures. Though the clinical pharmacokinetics of VPA has been well defined, information about pharmacokinetics after overdoses is rare.
The aim of this study was to try to build a population pharmacokinetic model that would describe the time course of VPA and its selected metabolites when the drug is ingested in an overdose situation.
Blood samples were collected during admission to the hospital and several times during treatment for poisoning (10 men and 10 women). The concentration of VPA and its metabolites were determined by liquid chromatography coupled with mass spectrometry. For population pharmacokinetic evaluation of VPA and its metabolites, the two-compartment-model was applied.
The estimated doses of VPA taken ranged from 6 to 65 g, while the time after ingestion ranged from 1 to 30 h. Results showed that the β-oxidation process exhibited Michaelis-Menten kinetics becoming saturated during acute intoxication. The same could not be said for the desaturation route. VPA therapy increased the Vmax for β-oxidation by 59% while decontamination appeared to be of moderate efficacy lowering the F value by 34% on the average.
None of the models perfectly described the experimental data. Important factors like the variable degree of protein binding by VPA could not be included in the models. The small number of subjects used in the study made the analysis of more covariates impossible.
Severe valproic acid poisoning
2004, Reanimation
L'incidence des intoxications par l'acide valproïque (AVP) a augmenté de plus de 129 % depuis 1995, notamment aux États-Unis. Environ 50 % des patients n'expriment que des effets mineurs, et la mortalité atteint 2 %. Les intoxications engageant le pronostic vital sont donc rares, et pas systématiquement liées à un taux plasmatique très élevé : certaines formes graves sont dues à une déviation métabolique par le biais d'un déficit secondaire en carnitine. La configuration spatiale de l'acide valproïque est proche de celle des acides gras avec lesquels il entre en compétition lors de son transport (lié à la carnitine), de son métabolisme intramitochondrial (β-oxydation) et de son élimination (lié à la carnitine). Il peut en résulter une déviation métabolique avec apparition d'une hyperammoniémie, d'une hyperlactatémie et d'un coma. La prescription de L-carnitine, associée au traitement symptomatique, peut alors supprimer cette déviation métabolique et corriger rapidement les troubles métaboliques. L'efficacité de la L-carnitine a été démontrée sur le plan expérimental et plusieurs cas cliniques ont montré son intérêt, mais aucune étude prospective et randomisée n'a pour l'instant été réalisée.
The incidence of valproic acid (VPA) intoxication has increased by more than 129% since 1995, particularly in the United States. Approximately 50% of the patients express only minor effects, and mortality reaches 2%. Life-threatening poisoning is thus rare, and not systematically related to a very high VPA plasmatic level: some severe forms are due to a metabolic diversion caused by a secondary deficit in carnitine. The structural configuration of VPA is close to that of the fatty acids. VPA may interfere with fatty acids during the transport (related to the carnitine), the intra-mitochondrial metabolism (β-oxidation) and the elimination steps (related to the carnitine). It can result in a metabolic diversion with the development of a hyperammoniemia, a hyperlactatemia and a coma. Infusion of l-carnitine, together with supportive treatment, could be helpful for the correction of the metabolic disorders. The effectiveness of l-carnitine was shown at the experimental level and several clinical cases suggested its usefulness, but a prospective and randomized study remains to be carried out.
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Research reportMetabolite profiles in patients on high-dose valproate monotherapy

Abstract

J. Pediatr.

Pediatr. Neurol.

Brain Dev.

Brain Dev.

J. Chromatogr.

Effect of valproate dose on formation of hepatotoxic metabolites

Epilepsia

Valproic acid hepatic fatalities: a retrospective review

Neurology

Valproate metabolites in serum and urine during antiepileptic therapy in children with infantile spasms: abnormal metabolite pattern associated with reversible hepatotoxicity

Epilepsia

Abnormal metabolism of valproic acid in fatal hepatic failure

Eur. J. Pediatr.

Association between risk factors for valproate hepatotoxicity and altered valproate metabolism

Epilepsia

Severe hepatotoxicity during valproate therapy: an update and report of eight new fatalities

Epilepsia

Research report
Metabolite profiles in patients on high-dose valproate monotherapy