title: Clinical significance of CYP2C9-status guided valproic acid therapy in children.
abstract: OBJECTIVE
  Valproic acid (VPA)-induced adverse effects, which are sometimes serious in children, can be associated with alterations in VPA metabolism. VPA-evoked toxicity is attributed to both the parent compound and its unsaturated metabolites, primarily formed by the cytochrome P450 (CYP)2C9 enzyme. Thus, patients' CYP2C9-status may account for the predisposition to adverse reactions, and testing CYP2C9-status may contribute to the improvement and rationalization of VPA therapy in children.
  
  
  METHODS
  In the CYPtest group, children's CYP2C9-status was screened before initiating antiepileptic therapy. CYP2C9-status was estimated by the identification of defective CYP2C9 allelic variants (CYP2C9*2, CYP2C9*3) and current CYP2C9 expression in patients' leukocytes, which reflects hepatic CYP2C9 activities. When the results of CYP2C9 genotyping and CYP2C9 expression were combined, the patients' VPA-metabolizing capacity was predicted, and VPA dosing was adjusted to the patients' CYP2C9-status. Clinical and biochemical parameters, such as VPA serum levels, blood cell counts, liver function parameters, and adverse effects in patients of CYPtest group were compared with those of the control group treated with VPA according to conventional clinical practice.
  
  
  RESULTS
  CYP2C9-guided treatment significantly reduced VPA misdosing and consequently decreased the ratio of patients out of the range of target VPA blood concentrations. In the CYPtest group of children who received CYP2C9-status adapted dose, serum alkaline phosphatase (ALP) level and the ratio of patients with abnormal ALP levels were substantially lower than in the control group. The incidence of serious side effects, notably hyperammonemia, was reduced in the CYPtest group; however, some other side effects, such as weight changes and somnolence, could not be avoided.
  
  
  CONCLUSIONS
  The knowledge of pediatric patients' CYP2C9-status can contribute to the optimization of VPA dosing and to the avoidance of misdosing-induced side effects.
authors.affiliation: 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Bűdi
authors.affiliation: Research Center for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Tóth
authors.affiliation: Heim Pál Children's Hospital, Budapest, Hungary.
authors.forename: Andrea
authors.initials: A
authors.lastname: Nagy
authors.affiliation: Heim Pál Children's Hospital, Budapest, Hungary.
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Szever
authors.affiliation: Research Center for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: Ádám
authors.initials: Á
authors.lastname: Kiss
authors.affiliation: Research Center for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: Manna
authors.initials: M
authors.lastname: Temesvári
authors.affiliation: Research Center for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: Edit
authors.initials: E
authors.lastname: Háfra
authors.affiliation: 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
authors.forename: Miklós
authors.initials: M
authors.lastname: Garami
authors.affiliation: Heim Pál Children's Hospital, Budapest, Hungary.
authors.forename: Adrienn
authors.initials: A
authors.lastname: Tapodi
authors.affiliation: Research Center for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Monostory
mesh_terms: D000293:Adolescent; D000927:Anticonvulsants / Q000097:blood / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics*; D064420:Drug-Related Side Effects and Adverse Reactions; D004827:Epilepsy / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D010597:Pharmacogenetics; D014635:Valproic Acid / Q000097:blood / Q000627:therapeutic use*
chemical_list: D000927:Anticonvulsants; D014635:Valproic Acid; D065729:Cytochrome P-450 CYP2C9
keywords: Anticonvulsant therapy; CYP2C9 expression; CYP2C9 genotype; Cytochrome P450; Personalized pharmacotherapy