Limin Liu1, Limei Zhao2, Qiuning Wang3, Feng Qiu1, Xiujun Wu4, Yanan Ma5. 1. Pharmacy Department, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning, China. 2. Pharmacy Department, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning, China. lmzhao19@163.com. 3. Subjects and Scientific Research Department, The First Affiliated Hospital of Liaoning Medical University, Jinzhou, China. 4. Clinical Pharmacokinetics Laboratory of traditional Chinese Medicine, Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, China. 5. Department of Biostatistics and Epidemiology, School of Public Health, China Medical University, Shenyang, China.
Abstract
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.
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 epilepticchildren. 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.
Authors: Sven C van Dijkman; Nico C B de Jager; Willem M Rauwé; Meindert Danhof; Oscar Della Pasqua Journal: Clin Pharmacokinet Date: 2018-08 Impact factor: 6.447
Authors: Sharmila Das; Dong Guo; Xiaohui Jiang; Wenlei Jiang; Yan Shu; Tricia Y Ting; James E Polli Journal: Pharm Res Date: 2020-02-26 Impact factor: 4.200
Authors: Daniel A Kelmenson; Kelsey Burr; Yusra Azhar; Paul Reynolds; Chelsea A Baker; Neda Rasouli Journal: J Investig Med High Impact Case Rep Date: 2017-06-08