title: Evaluation of valproate effects on acylcarnitine in epileptic children by LC-MS/MS.
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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pediatrics and Neonatology, Nagoya City University, Graduate School of Medical Sciences, Mizuho-cho, Nagoya, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Nakajima
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ito
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Maeda
authors.forename: Sayaka
authors.initials: S
authors.lastname: Ichiki
authors.forename: Satoru
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Naoki
authors.initials: N
authors.lastname: Ando
authors.forename: Mohamed Hamed
authors.initials: MH
authors.lastname: Hussein
authors.forename: Yukihisa
authors.initials: Y
authors.lastname: Kurono
authors.forename: Naruji
authors.initials: N
authors.lastname: Sugiyama
authors.forename: Hajime
authors.initials: H
authors.lastname: Togari
mesh_terms: D000293:Adolescent; D000927:Anticonvulsants / Q000627:therapeutic use*; D002331:Carnitine / Q000031:analogs & derivatives* / Q000097:blood; D002648:Child; D002675:Child, Preschool; D002853:Chromatography, Liquid / Q000379:methods; D004827:Epilepsy / Q000097:blood* / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007223:Infant; D016014:Linear Models; D008137:Longitudinal Studies; D008297:Male; D018709:Statistics, Nonparametric; D053719:Tandem Mass Spectrometry / Q000379:methods; D014635:Valproic Acid / Q000627:therapeutic use*
chemical_list: C098116:3-hydroxyisovalerylcarnitine; D000927:Anticonvulsants; C116917:acylcarnitine; D014635:Valproic Acid; C044923:valproylcarnitine; D002331:Carnitine