title: Apparent autoinduction of valproate beta-oxidation in humans.
abstract: OBJECTIVE
  The study aimed to show whether autoinduction of valproate (VPA) along its beta-oxidation pathway occurred upon chronic dosing in humans.
  
  
  METHODS
  Twelve young volunteers without active illness took sodium valproate (NaVPA) 200 mg orally 12 hourly for 3 weeks. On days 7 and 21, serial blood samples and all urine passed over an interdosing interval from 08.00 to 20.00 h were collected for analysis of VPA and certain metabolites.
  
  
  RESULTS
  Plasma AUC(0,12 h) of VPA was significantly lower on day 21 than on day 7 (2.40 vs 2.84 micromol ml-1 h, 95% CI for the difference 0.13-0.81 micromol ml-1 h). Significant differences in plasma AUC(0,12 h) of the beta-oxidation metabolites E-2-en-VPA and 3-oxo-VPA were not found. However, formation clearances of plasma VPA to urinary E-2-en-VPA and 3-oxo-VPA were significantly increased from day 7 to day 21 (0. 010 vs 0.024 and 2.57 vs 3.60 ml kg-1 h-1, respectively, 95% CI for the differences -0.025 to -0.004 and -1.72 to -0.34 ml kg-1 h-1, respectively). Formation clearances to VPA-glucuronide (0.534 vs 0. 505 ml kg-1 h-1) and 4-OH-VPA (0.112 vs 0.110 ml kg-1 h-1) were not significantly different.
  
  
  CONCLUSIONS
  Regular low dose VPA intake in humans over a period of 3 weeks appears to be associated with a small induction of its metabolism by the beta-oxidation pathway, but not by glucuronidation or 4-hydroxylation.
authors.affiliation: Centre for Studies in Drug Disposition, Department of Medicine, University of Queensland at Royal Brisbane Hospital, Clinical Sciences Building, Royal Brisbane Hospital, QLD 4029, Australia.
authors.forename: D B
authors.initials: DB
authors.lastname: McLaughlin
authors.forename: J A
authors.initials: JA
authors.lastname: Andrews
authors.forename: W D
authors.initials: WD
authors.lastname: Hooper
authors.forename: G R
authors.initials: GR
authors.lastname: Cannell
authors.forename: M J
authors.initials: MJ
authors.lastname: Eadie
authors.forename: R G
authors.initials: RG
authors.lastname: Dickinson
mesh_terms: D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D010084:Oxidation-Reduction; D014635:Valproic Acid / Q000493:pharmacokinetics*
chemical_list: D000927:Anticonvulsants; D014635:Valproic Acid