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Determinants of Variability in Divalproex Sodium (VPA) Glucuronidation in Children

Sources of variability in VPA glucuronidation (VPA‐G) were investigated in 92 children (38F, 54M) treated with VPA for seizure disorders. Urine collected over a steady state dosing interval was analyzed for VPA and 15 metabolites by LC‐ and GC‐MS. DNA in a subset of patients (n=47) was genotyped for UGT1A6, UGT1A9, and UGT2B7 SNPs, and UGT2B17 copy number variation (CNV). IRB approval was obtained at each clinical site. Urinary VPA‐G concentration (nmol/mg creatinine) varied 800‐fold and accounted for 62.5±17.9% (mean±SD) of the total molar recovery of drug and metabolites. VPA‐G concentrations correlated with daily dose (mg/kg; p<0.0001), increased with concurrent enzyme‐inducing medications (p<0.001) and 2 copies of UGT2B17 (p<0.05), and decreased with age (p<0.05). By contrast, no age association was observed with fractional recovery of VPA‐G although dose, enzyme‐inducing meds and UGT2B17 CNV remained significant. A general linear model confirmed the associations between fraction recovery of VPA‐G and dose (p=0.006) and UGT2B17 CNV (p=0.031). VPA dose is the primary determinant of VPA‐G variability in children, and UGT2B17 copy number may also contribute. Supported by grant HD044239 from NICHD.