Effects of Valproate on Acylcarnitines in Children with Epilepsy Using ESI‐MS/MS

Abstract

Summary:Purpose: To determine the influence of valproate (VPA) treatment on acylcarnitines in children with epilepsy.Methods: Determination of acylcarnitines (including free carnitine and acylcarnitines from C2 to C18) in dried blood spot specimens using tandem-mass spectrometry. Longitudinal study of changes in acylcarnitines in children under VPA treatment without pretreatment (group 1) or with pretreatment with other antiepileptic drugs (group 2) before the start of VPA treatment at an early and a late treatment interval (12-66, 90-260 days after the beginning of treatment, respectively). Cross-sectional comparison of these two VPA groups and of a group receiving carbamazepine monotherapy (group 3) with controls.Results: Acylcarnitines in epileptic patients before VPA therapy did not differ from control values. In group 1, decreases of C0 (−26%), C2 (−12%), C16 (−31%), C18 (−41%), C total (−10%), increases of C5OH (+31%), C8 (+33%) in the early treatment interval, and decreases of C16 (−21%), C18 (−42%), and increases of C2 (+26%), C5OH (+44%) in the late treatment interval were significant. In group 2, both in the longitudinal and the cross-sectional study, only a decrease of C18 (−41%, −43%, respectively) in the late treatment interval was found. In group 3, no significant changes have been observed.Conclusions: We could prove changes in acylcarnitine subspecies, which were associated with VPA treatment in children with epilepsy. The treatment interval with the most marked changes coincides with the interval of highest risk for VPA-induced hepatotoxicity. The observed specific acylcarnitine pattern might point to the impaired intermediary metabolism that is responsible for VPA-induced hepatotoxicity.

Targeted Liquid Chromatography–Mass Spectrometry Analysis of Serum Acylcarnitines in Acetaminophen Toxicity in Children

“…In the mouse model of APAP toxicity, oleoyl-, palmitoyl- and myristoyl-carnitines were observed to be significantly increased over the course of toxicity [16]. However, a major difference in the animal model and the clinical setting of APAP toxicity is the impact of treatment with NAC.…”

“…For example, pediatric diseases or conditions known to be associated with impaired mitochondrial function could be examined with this approach in the future. In addition, similar approaches could be applied to study other drugs (e.g., valproic acid) that are widely used in children and are known to have effects on mitochondria and to cause liver injury [16]. Therefore, future studies should examine metabolomicbased metabolites in relation to indicators of drug metabolism and liver injury.…”

“…Acylcarnitines are intermediates in the mitochondrial α-oxidation of fatty acids and have been postulated as indicators of hepatotoxicity in APAP [9,13–15] and other drugs such as valproic acid [16] that are known to have effects on mitochondria. A liquid chromatography–mass spectrometry (LC/MS)-based metabolomics study of APAP metabolism in wild-type and Cyp2E1-null mice revealed that acylcarnitines can function as complementary biomarkers for APAP-induced hepatotoxicity [17].…”

Drug–Nutrient Interactions: A Broad View with Implications for Practice

“…This has been better described with the older agents (eg, carbamazepine, phenobarbital, phenytoin) than the newer ones (31)(32)(33)(34). Valproic acid treatment is associated with carnitine deficiency and altered acylcarnitine subspecies that reflect impaired intermediary metabolism likely responsible for drug-induced hepatotoxicity and hyperammonemia (128,129). The influence on the status of a nutrient in these circumstances may or may not be adequately addressed by nutrient supplementation while the patient is taking the drug (51,130,131).…”

Drug and nutrition interactions: not just food for thought

“…valproic acid) may result from carnitine deficits. 41,42 Adverse drug effects explained by drug-induced nutrient deficits continue to be explored.…”