Evaluation of valproate effects on acylcarnitine in epileptic children by LC-MS/MS

Yoko Nakajima, Tetsuya Ito, Yasuhiro Maeda, Sayaka Ichiki, Satoru Kobayashi, Naoki Ando, Mohamed Hamed Hussein, Yukihisa Kurono, Naruji Sugiyama, Hajime Togari

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Background: Valproate (VPA) is a simple fatty acid and a substrate for the fatty acid β-oxidation pathway. Previous data suggested that the toxicity of VPA may be provoked by carnitine deficiency and the inhibition of mitochondrial β-oxidation. Objective: The aim of the present study was to elucidate the effect of VPA treatment on carnitine and isomer-differentiated acylcarnitine disposition, and determined the relationships between acylcarnitines and blood VPA levels in long-term treated patients with VPA and/or other antiepileptic drugs. Methods: Serum samples were obtained from children aged 1-15. years old treated for at least 6. months with VPA alone (n=28) or VPA combined with other anticonvulsants (n=23) and untreated controls (n=23). Serum acylcarnitines were separated from their isomers and quantified using high-performance liquid chromatography-tandem mass spectrometry. Results: We found higher 3-hydroxyisovalerylcarnitine levels and trace amounts of valproylcarnitine in both VPA monotherapy and polytherapy patients. Other acylcarnitines, hexanoylcarnitine, C12, C14:1-carnitines and the ratio of long-chain acylcarnitine to free carnitine were also higher in VPA polytherapy individuals than in controls. VPA monotherapy does not result in decreases in free carnitine or in the accumulation of long-chain acylcarnitines. Blood VPA concentrations correlated positively with hexanoylcarnitine, C12, C14:1, C16:1, C18:1-carnitines in all VPA-treated children (n=51). Conclusion: Long-term VPA treatment in pediatric patients could affect some specific acylcarnitines, which is enhanced by the concomitant use of other anticonvulsants, and the formation of valproylcarnitine alone seems insufficient to develop severe carnitine deficiency at therapeutic doses of VPA.

Original languageEnglish
Pages (from-to)816-823
Number of pages8
JournalBrain and Development
Volume33
Issue number10
DOIs
Publication statusPublished - 01-11-2011

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Valproic Acid
Carnitine
Anticonvulsants
acylcarnitine
Fatty Acids
Tandem Mass Spectrometry
Serum
Therapeutics

All Science Journal Classification (ASJC) codes

  • Pediatrics, Perinatology, and Child Health
  • Developmental Neuroscience
  • Clinical Neurology

Cite this

Nakajima, Y., Ito, T., Maeda, Y., Ichiki, S., Kobayashi, S., Ando, N., ... Togari, H. (2011). Evaluation of valproate effects on acylcarnitine in epileptic children by LC-MS/MS. Brain and Development, 33(10), 816-823. https://doi.org/10.1016/j.braindev.2010.12.003
Nakajima, Yoko ; Ito, Tetsuya ; Maeda, Yasuhiro ; Ichiki, Sayaka ; Kobayashi, Satoru ; Ando, Naoki ; Hussein, Mohamed Hamed ; Kurono, Yukihisa ; Sugiyama, Naruji ; Togari, Hajime. / Evaluation of valproate effects on acylcarnitine in epileptic children by LC-MS/MS. In: Brain and Development. 2011 ; Vol. 33, No. 10. pp. 816-823.
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abstract = "Background: Valproate (VPA) is a simple fatty acid and a substrate for the fatty acid β-oxidation pathway. Previous data suggested that the toxicity of VPA may be provoked by carnitine deficiency and the inhibition of mitochondrial β-oxidation. Objective: The aim of the present study was to elucidate the effect of VPA treatment on carnitine and isomer-differentiated acylcarnitine disposition, and determined the relationships between acylcarnitines and blood VPA levels in long-term treated patients with VPA and/or other antiepileptic drugs. Methods: Serum samples were obtained from children aged 1-15. years old treated for at least 6. months with VPA alone (n=28) or VPA combined with other anticonvulsants (n=23) and untreated controls (n=23). Serum acylcarnitines were separated from their isomers and quantified using high-performance liquid chromatography-tandem mass spectrometry. Results: We found higher 3-hydroxyisovalerylcarnitine levels and trace amounts of valproylcarnitine in both VPA monotherapy and polytherapy patients. Other acylcarnitines, hexanoylcarnitine, C12, C14:1-carnitines and the ratio of long-chain acylcarnitine to free carnitine were also higher in VPA polytherapy individuals than in controls. VPA monotherapy does not result in decreases in free carnitine or in the accumulation of long-chain acylcarnitines. Blood VPA concentrations correlated positively with hexanoylcarnitine, C12, C14:1, C16:1, C18:1-carnitines in all VPA-treated children (n=51). Conclusion: Long-term VPA treatment in pediatric patients could affect some specific acylcarnitines, which is enhanced by the concomitant use of other anticonvulsants, and the formation of valproylcarnitine alone seems insufficient to develop severe carnitine deficiency at therapeutic doses of VPA.",
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Nakajima, Y, Ito, T, Maeda, Y, Ichiki, S, Kobayashi, S, Ando, N, Hussein, MH, Kurono, Y, Sugiyama, N & Togari, H 2011, 'Evaluation of valproate effects on acylcarnitine in epileptic children by LC-MS/MS', Brain and Development, vol. 33, no. 10, pp. 816-823. https://doi.org/10.1016/j.braindev.2010.12.003

Evaluation of valproate effects on acylcarnitine in epileptic children by LC-MS/MS. / Nakajima, Yoko; Ito, Tetsuya; Maeda, Yasuhiro; Ichiki, Sayaka; Kobayashi, Satoru; Ando, Naoki; Hussein, Mohamed Hamed; Kurono, Yukihisa; Sugiyama, Naruji; Togari, Hajime.

In: Brain and Development, Vol. 33, No. 10, 01.11.2011, p. 816-823.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Evaluation of valproate effects on acylcarnitine in epileptic children by LC-MS/MS

AU - Nakajima, Yoko

AU - Ito, Tetsuya

AU - Maeda, Yasuhiro

AU - Ichiki, Sayaka

AU - Kobayashi, Satoru

AU - Ando, Naoki

AU - Hussein, Mohamed Hamed

AU - Kurono, Yukihisa

AU - Sugiyama, Naruji

AU - Togari, Hajime

PY - 2011/11/1

Y1 - 2011/11/1

N2 - Background: Valproate (VPA) is a simple fatty acid and a substrate for the fatty acid β-oxidation pathway. Previous data suggested that the toxicity of VPA may be provoked by carnitine deficiency and the inhibition of mitochondrial β-oxidation. Objective: The aim of the present study was to elucidate the effect of VPA treatment on carnitine and isomer-differentiated acylcarnitine disposition, and determined the relationships between acylcarnitines and blood VPA levels in long-term treated patients with VPA and/or other antiepileptic drugs. Methods: Serum samples were obtained from children aged 1-15. years old treated for at least 6. months with VPA alone (n=28) or VPA combined with other anticonvulsants (n=23) and untreated controls (n=23). Serum acylcarnitines were separated from their isomers and quantified using high-performance liquid chromatography-tandem mass spectrometry. Results: We found higher 3-hydroxyisovalerylcarnitine levels and trace amounts of valproylcarnitine in both VPA monotherapy and polytherapy patients. Other acylcarnitines, hexanoylcarnitine, C12, C14:1-carnitines and the ratio of long-chain acylcarnitine to free carnitine were also higher in VPA polytherapy individuals than in controls. VPA monotherapy does not result in decreases in free carnitine or in the accumulation of long-chain acylcarnitines. Blood VPA concentrations correlated positively with hexanoylcarnitine, C12, C14:1, C16:1, C18:1-carnitines in all VPA-treated children (n=51). Conclusion: Long-term VPA treatment in pediatric patients could affect some specific acylcarnitines, which is enhanced by the concomitant use of other anticonvulsants, and the formation of valproylcarnitine alone seems insufficient to develop severe carnitine deficiency at therapeutic doses of VPA.

AB - Background: Valproate (VPA) is a simple fatty acid and a substrate for the fatty acid β-oxidation pathway. Previous data suggested that the toxicity of VPA may be provoked by carnitine deficiency and the inhibition of mitochondrial β-oxidation. Objective: The aim of the present study was to elucidate the effect of VPA treatment on carnitine and isomer-differentiated acylcarnitine disposition, and determined the relationships between acylcarnitines and blood VPA levels in long-term treated patients with VPA and/or other antiepileptic drugs. Methods: Serum samples were obtained from children aged 1-15. years old treated for at least 6. months with VPA alone (n=28) or VPA combined with other anticonvulsants (n=23) and untreated controls (n=23). Serum acylcarnitines were separated from their isomers and quantified using high-performance liquid chromatography-tandem mass spectrometry. Results: We found higher 3-hydroxyisovalerylcarnitine levels and trace amounts of valproylcarnitine in both VPA monotherapy and polytherapy patients. Other acylcarnitines, hexanoylcarnitine, C12, C14:1-carnitines and the ratio of long-chain acylcarnitine to free carnitine were also higher in VPA polytherapy individuals than in controls. VPA monotherapy does not result in decreases in free carnitine or in the accumulation of long-chain acylcarnitines. Blood VPA concentrations correlated positively with hexanoylcarnitine, C12, C14:1, C16:1, C18:1-carnitines in all VPA-treated children (n=51). Conclusion: Long-term VPA treatment in pediatric patients could affect some specific acylcarnitines, which is enhanced by the concomitant use of other anticonvulsants, and the formation of valproylcarnitine alone seems insufficient to develop severe carnitine deficiency at therapeutic doses of VPA.

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