title: The effect of uridine diphosphate glucuronosyltransferase (UGT)1A6 genetic polymorphism on valproic acid pharmacokinetics in Indian patients with epilepsy: a pharmacogenetic approach.
abstract: OBJECTIVE
  Sodium valproate is a widely prescribed broad-spectrum antiepileptic drug. It shows high inter-individual variability in pharmacokinetics and pharmacodynamics and has a narrow therapeutic range. We evaluated the effects of polymorphic uridine diphosphate glucuronosyltransferase (UGT)1A6 (541A>G, 552A>C) metabolizing enzyme on the pharmacokinetics of sodium valproate in the patients with epilepsy who showed toxicity to therapy.
  
  
  METHODS
  Genotype analysis of the patients was made with polymerase chain-restriction fragment length polymorphism (RFLP) with sequencing. Plasma drug concentrations were measured with reversed phase high-performance liquid chromatography (HPLC) and concentration-time data were analyzed by using a non-compartmental approach.
  
  
  RESULTS
  The results of this study suggested a significant genotypic as well as allelic association with valproic acid toxicity for UGT1A6 (541A>G) or UGT1A6 (552A>C) polymorphic enzymes. The elimination half-life (t ½ = 40.2 h) of valproic acid was longer and the clearance rate (CL = 917 ml/h) was lower in the poor metabolizers group of UGT1A6 (552A>C) polymorphism who showed toxicity than in the intermediate metabolizers group (t ½ = 35.5 h, CL = 1,022 ml/h) or the extensive metabolizers group (t ½ = 25.4 h, CL = 1,404 ml/h).
  
  
  CONCLUSIONS
  Our findings suggest that the UGT1A6 (552A>C) genetic polymorphism plays a significant role in the steady state concentration of valproic acid, and it thereby has an impact on the toxicity of the valproic acid used in the patients with epilepsy.
authors.affiliation: Department of Neurobiochemistry, Neurosciences Center, All India Institute of Medical Sciences, New Delhi, 110029, India.
authors.forename: Murali
authors.initials: M
authors.lastname: Munisamy
authors.forename: Manjari
authors.initials: M
authors.lastname: Tripathi
authors.forename: Madhuri
authors.initials: M
authors.lastname: Behari
authors.forename: S
authors.initials: S
authors.lastname: Raghavan
authors.forename: D C
authors.initials: DC
authors.lastname: Jain
authors.forename: Barghavi
authors.initials: B
authors.lastname: Ramanujam
authors.forename: Karthik
authors.initials: K
authors.lastname: Arumugam
authors.forename: Thiyagu
authors.initials: T
authors.lastname: Rajakannan
authors.forename: Surulivel Rajan
authors.initials: SR
authors.lastname: Mallayasamy
authors.forename: Vivekanandhan
authors.initials: V
authors.lastname: Subbiah
mesh_terms: D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D002648:Child; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D007194:India; D008297:Male; D020641:Polymorphism, Single Nucleotide; D014635:Valproic Acid / Q000037:antagonists & inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D014635:Valproic Acid; C110655:UDP-glucuronosyltransferase, UGT1A6; D014453:Glucuronosyltransferase