Impact of Age and Genotype on Serum Concentrations of Valproic Acid and Its Hepatotoxic Metabolites in Chinese Pediatric Patients With Epilepsy

Background: The aim of the study was to investigate how age and genetic polymorphisms of UGT1A6 and UGT2B7 contribute to the concentrations of valproic acid (VPA) and its hepatotoxic metabolites in Chinese pediatric patients with epilepsy. Methods: A total of 122 children with epilepsy were genotyped at 19T>G, 541A>G, and 552A>C in UGT1A6 and -161C>T and 802C>T in UGT2B7 using the polymerase chain reaction-restriction fragment length polymorphism method or direct sequencing method. The concentrations of VPA, 4-ene-VPA, and 2,4-diene-VPA were simultaneously determined using ultra-performance liquid chromatography-tandem mass spectrometry. Results: Significant association was observed between the UGT2B7 802C>T genotype and dose-adjusted concentrations of VPA, 4-ene-VPA, and 2,4-diene-VPA. The younger children had increased concentrations of the hepatotoxic metabolites and decreased levels of VPA. The allele status of UGT2B7 802C>T had no influence on the metabolite ratios within age groups, but showed a significant difference among the age groups. Conclusions: The present study suggests that UGT2B7 802C>T polymorphism and age are factors affecting the concentrations of dose-adjusted VPA and its metabolites. No genotype-related differences were noted in the metabolite ratios of 4-ene-VPA and 2,4-diene-VPA within age-assigned groups. Therefore, careful administration is particularly necessary for younger patients who are UGT2B7 802C>T poor metabolizers.