(The FASEB Journal. 2008;22:1131.7)
© 2008 FASEB
(The FASEB Journal. 2008;22:1131.7.)
© 2008 FASEB
Variability in valproic acid (VPA) metabolite signatures in children
James Steven Leeder1,
Andrea Gaedigk1,
Robin E. Pearce1,
Frank S. Abbott2,
Thomas K.H. Chang2,
Tony Kiang2,
XiaoWei Teng2,
Mary Jayne Kennedy3 and
Robert M. Ward4
1 Pediatrics, Children’s Mercy Hospitals and Clinics, Kansas City, MO
2 Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada
3 Pediatric Pharmacology, Kosair Children’s Hospital, Louisville, KY
4 University of Utah, Salt Lake City, UT
ABSTRACT
VPA is associated with an idiosyncratic hepatotoxicity that is most prevalent in children under 2 years of age receiving concurrent enzyme-inducing anti-epileptic drugs. The goal of this study was to establish the limits of normal variability in VPA metabolite patterns in a population of children. Urine was collected over a steady state dosing interval in 91 pediatric patients aged 2 to 17 years receiving VPA either as monotherapy or polytherapy, and analyzed by GC-MS methods for VPA and 14 metabolites. Principal components analysis of the log-transformed metabolite data (corrected for urinary creatinine) revealed three distinct clusters of metabolites generally corresponding to microsomal biotransformation, mitochondrial beta-oxidation, and N-acetylcysteine (NAC) metabolites derived from glutathione (GSH)-conjugates of (E)-2,4-diene. If NAC conjugates are the products of reactive metabolite formation and GSH conjugation in mitochondria and free 2,4-diene-VPA is derived from a non-reactive microsomal pathway, we hypothesize that the NAC-VPA/2,4-diene ratio may reflect interindividual variability in bioactivation and detoxification capacity. A Q-Q plot of the log-transformed ratio implies a bimodal distribution that is being evaluated as a potential biomarker for VPA-toxicity in this population.
Supported by grant U01 HD-044239 from NICHD
