Impact Of CYP2C19 Genotypes On Serum Concentrations Of Valproic Acid In Epileptic Children

Objective:To investigate the relationship between sodium valproate(VPA)and cytochrome P450 2C19(CYP2C19)gene polymorphisms and to explore the impact of age and gender on VPA plasma concentration in children with epilepsy,so as to guide individualized treatment based on these factors.Methods: 1.Data was retrospectively collected during the period March,2012~February,2017 in patients who had been subjected to monitoring of VPA.The concentration of VPA in blood was measured by enzyme amplification immunoassay.CYP2C19 gene(* l,* 2,* 3)as detected by gene chip technology.Children were divided into three groups according to genotypes: extensive metabolizer(EM)(1 / * 1)intermediate metabolizer(IM)(1 / 2,* 1 / * 3)and poor metabolizer(PM)(* 2 / * 2,* 2 / * 3,* 3 / * 3).2.Variance analysis was used to compare the differences in the plasma concentration of VPA between different metabolic,different age and different sexes.3.Stepwise multivariate regression analysis was used to investigate correlation between differences in metabolic patterns,ages and genders.Results: 1.General condition: 36 patients(18 males,18 femals)were included in the study.Age ranged between 0.79 and 12 years old,median of 6.83 years old.VPA plasma concentration ranged between 38 and 130?g/ml,median of 77?g/ml.VPA maintenance dose ranged between 12.31 and 56.60 mg/(kg·d),median of 18.87mg/(kg·d).2.Genotype distribution: The frequencies of the alleles in all the cases included were in accordance with Hardy-Weinberg's law of equilibrium(X2 = 1.19,P> 0.05).We found that there were five genotypes in two mutations of CYP2C19: * 1 / * 1,*1 / * 2,* 1 / * 3,* 2 / * 2,* 2 / * 3 type,and * 3 / * 3 type was not found.The distribution frequencies of EMs phenotype(* 1 / * 1),IMs phenotype(* 1 / 2,* 1 / * 3)and PMs(* 2 / * 2,* 2 / * 3,* 3 / * 3)phenotype were 41.66%,38.89% and 19.45%,respectively.There was no significant difference in distribution of different CYP2C19 genotypes between different genders(P> 0.05).3.Influencing factors of VPA plasma concentration:VPA standardized plasma concentrations of EM,IM and PM group was(4.03 ± 1.06),(4.06 ± 1.44)and(3.48 ± 1.95)?g/ml respectively.There was no significant difference in VPA standardized plasma concentration between different genetype groups(F = 0.450,P = 0.642> 0.05).VPA standardized plasma concentration of male and female was(3.17±1.30),(4.70±1.01)?g/mlrespectively.And T Test showed that the differences were statistical significance(P<0.05).VPA standardized plasma concentrations of 0 ~ 1 years old,1 ~ 10 years old and 10 ~ 14 years old group was(3.74 ± 1.45),(3.81 ± 1.26),(3.79 ± 1.62)?g/ml,respectively.However,the result showed no statistical significance(P> 0.05).4.Multiple stepwise regression analysis: Regression model:Standardized plasma concentration = 4.702-1.529 × gender(male-1,female-0).Based on the regression model,gender has significantly influence on the VPA serum concentration of children.CYP2C19 genotypes and age did not influence the VPA serum concentrationsignificantly.Conclusion: The present study revealed that VPA serum concentration was significantly influenced by gender,while CYP2C19 genotype and age have no significantly influence on VPA serum concentration in our study.