Influence of valproic acid concentration and polymorphism of UGT1A4*3, UGT2B7 -161C > T and UGT2B7*2 on serum concentration of lamotrigine in Chinese epileptic children.

PURPOSE: To investigate the impact of valproic acid (VPA) and genetic polymorphism of the major metabolizing enzyme (UGT1A4, UGT2B7) of lamotrigine (LTG) and VPA on LTG concentration in Chinese epileptic children.

METHODS

Three single nucleotide polymorphisms (UGT1A4*3, UGT2B7 -161C > T and UGT2B7*2) were analyzed by polymerase chain reaction-restriction fragment length polymorphism or direct DNA sequencing. The concentrations of LTG and VPA were measured by high-performance liquid chromatography (HPLC) and fluorescence polarization immunoassay, respectively. The adjusted concentration of LTG was defined as the concentration-to-dose-ratio (CDRLTG). Data analysis was performed using IBM SPSS Statistics 21.0.

RESULTS

A total of 56 patients treated with LTG as monotherapy and 158 patients treated with LTG plus VPA were included in this study. In the polytherapy group, LTG concentration showed a good linear relationship with gender, age, daily LTG dose, VPA concentration, and UGT1A4*3 polymorphism, but had no relationship with the polymorphism of UGT2B7 -161C > T or UGT2B7*2. Moreover, LTG concentration and CDRLTG for the UGT1A4*3 were higher compared to UGT1A4*1 (LTG: 7.24 ± 3.51 vs 5.26 ± 3.27 μg/mL, p = 0.001; CDRLTG: 2.75 ± 1.02 vs 2.14 ± 0.96 μg/mL per mg/kg, p < 0.001, respectively). In the monotherapy group, there was no statistical difference between UGT1A4*3 and UGT1A4*1 in LTG concentration or CDRLTG. The patients in the polytherapy group were divided into two subgroups according to VPA concentration (lower/higher: 10-50/50-125 μg/mL). CDRLTG values of the patients carrying the UGT1A4*3 genotype were higher compared to UGT1A4*1*1 (2.86 ± 1.03 vs 2.22 ± 0.94 μg/mL per mg/kg, p = 0.001) only when the VPA concentration was higher.

CONCLUSIONS

UGT1A4*3 polymorphism had an effect on LTG concentration only with VPA co-administration, and the effect was remarkable when VPA concentration was higher.