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Effects of valproic acid on organic acid metabolism in children: a metabolic profiling study.

Price KE, Pearce RE, Garg UC, Heese BA, Smith LD, Sullivan JE, Kennedy MJ, Bale JF, Ward RM, Chang TK, Abbott FS, Leeder JS - Clin. Pharmacol. Ther. (2011)

Bottom Line: Age-matched patients receiving treatment with carbamazepine (CBZ; n = 50) and healthy children not undergoing treatment (n = 22) served as controls.Although the untreated and CBZ control groups were indistinguishable from each other with respect to the principal-component analysis (PCA) score plots of the subjects, a distinct boundary was apparent between the VPA and each of the control groups.Interindividual variability was observed in the VPA-induced alterations in endogenous pathways corresponding to branched-chain amino acid metabolism and oxidative stress.

View Article: PubMed Central - PubMed

Affiliation: Division of Clinical Pharmacology and Medical Toxicology, Department of Pediatrics, Children's Mercy Hospitals and Clinics, Kansas City, Missouri, USA.

ABSTRACT
Young children are at increased risk for valproic acid (VPA) hepatotoxicity. Urinary organic acid profiles, as a surrogate of mitochondrial function, were obtained in children 1.9 to 17.3 years of age (n = 52) who were undergoing treatment with VPA for seizure disorders. Age-matched patients receiving treatment with carbamazepine (CBZ; n = 50) and healthy children not undergoing treatment (n = 22) served as controls. Age-related changes in organic acid profiles were observed in all three groups. Although the untreated and CBZ control groups were indistinguishable from each other with respect to the principal-component analysis (PCA) score plots of the subjects, a distinct boundary was apparent between the VPA and each of the control groups. Interindividual variability was observed in the VPA-induced alterations in endogenous pathways corresponding to branched-chain amino acid metabolism and oxidative stress. The data suggest that more detailed metabolomic analysis may provide novel insights into biological mechanisms and predictive biomarkers for children at highest risk for serious toxicity.

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Age trends identified by principal components analysis (PCA). Subject age was regressed against PC1 scores separately for each group: Control (), CBZ (), and VPA (). The lines of best fit for each group are colored according to the color of the symbol for that group. The similarity in the slopes of the regressed lines indicates that age-related changes in organic acid profiles were similar in each group, and independent of drug treatment.
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Figure 1: Age trends identified by principal components analysis (PCA). Subject age was regressed against PC1 scores separately for each group: Control (), CBZ (), and VPA (). The lines of best fit for each group are colored according to the color of the symbol for that group. The similarity in the slopes of the regressed lines indicates that age-related changes in organic acid profiles were similar in each group, and independent of drug treatment.

Mentions: A principal component model was generated, and the principal components were then regressed against age. The first principal component (PC1) accounted for 31.2% of the variance and showed a highly significant age trend (p<0.0001) with an r value of −0.55. PC1 was primarily defined by 2-hydroxyglutaric, 3-hydroxyisobutyric, 3-hydroxyisovaleric and glutaric acids. All organic acids were negatively correlated with age, signifying that their rate of change was invariant with age, or was slower than the developmental increase in creatinine. When PC1 was regressed with subject age, the trends were parallel for the VPA and control groups (Figure 1). These results indicate that age-related changes in urinary organic acid profiles were preserved in all three groups, and further imply that this relationship was not affected by drug administration.


Effects of valproic acid on organic acid metabolism in children: a metabolic profiling study.

Price KE, Pearce RE, Garg UC, Heese BA, Smith LD, Sullivan JE, Kennedy MJ, Bale JF, Ward RM, Chang TK, Abbott FS, Leeder JS - Clin. Pharmacol. Ther. (2011)

Age trends identified by principal components analysis (PCA). Subject age was regressed against PC1 scores separately for each group: Control (), CBZ (), and VPA (). The lines of best fit for each group are colored according to the color of the symbol for that group. The similarity in the slopes of the regressed lines indicates that age-related changes in organic acid profiles were similar in each group, and independent of drug treatment.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3822904&req=5

Figure 1: Age trends identified by principal components analysis (PCA). Subject age was regressed against PC1 scores separately for each group: Control (), CBZ (), and VPA (). The lines of best fit for each group are colored according to the color of the symbol for that group. The similarity in the slopes of the regressed lines indicates that age-related changes in organic acid profiles were similar in each group, and independent of drug treatment.
Mentions: A principal component model was generated, and the principal components were then regressed against age. The first principal component (PC1) accounted for 31.2% of the variance and showed a highly significant age trend (p<0.0001) with an r value of −0.55. PC1 was primarily defined by 2-hydroxyglutaric, 3-hydroxyisobutyric, 3-hydroxyisovaleric and glutaric acids. All organic acids were negatively correlated with age, signifying that their rate of change was invariant with age, or was slower than the developmental increase in creatinine. When PC1 was regressed with subject age, the trends were parallel for the VPA and control groups (Figure 1). These results indicate that age-related changes in urinary organic acid profiles were preserved in all three groups, and further imply that this relationship was not affected by drug administration.

Bottom Line: Age-matched patients receiving treatment with carbamazepine (CBZ; n = 50) and healthy children not undergoing treatment (n = 22) served as controls.Although the untreated and CBZ control groups were indistinguishable from each other with respect to the principal-component analysis (PCA) score plots of the subjects, a distinct boundary was apparent between the VPA and each of the control groups.Interindividual variability was observed in the VPA-induced alterations in endogenous pathways corresponding to branched-chain amino acid metabolism and oxidative stress.

View Article: PubMed Central - PubMed

Affiliation: Division of Clinical Pharmacology and Medical Toxicology, Department of Pediatrics, Children's Mercy Hospitals and Clinics, Kansas City, Missouri, USA.

ABSTRACT
Young children are at increased risk for valproic acid (VPA) hepatotoxicity. Urinary organic acid profiles, as a surrogate of mitochondrial function, were obtained in children 1.9 to 17.3 years of age (n = 52) who were undergoing treatment with VPA for seizure disorders. Age-matched patients receiving treatment with carbamazepine (CBZ; n = 50) and healthy children not undergoing treatment (n = 22) served as controls. Age-related changes in organic acid profiles were observed in all three groups. Although the untreated and CBZ control groups were indistinguishable from each other with respect to the principal-component analysis (PCA) score plots of the subjects, a distinct boundary was apparent between the VPA and each of the control groups. Interindividual variability was observed in the VPA-induced alterations in endogenous pathways corresponding to branched-chain amino acid metabolism and oxidative stress. The data suggest that more detailed metabolomic analysis may provide novel insights into biological mechanisms and predictive biomarkers for children at highest risk for serious toxicity.

Show MeSH
Related in: MedlinePlus