title: Polymorphisms of ABCG2, ABCB1 and HNF4α are associated with Lamotrigine trough concentrations in epilepsy patients.
abstract: Lamotrigine (LTG) is commonly used to control seizure in epilepsy patients and with referenced therapeutic windows in clinical practice. This study is to identify and characterize the function of genetic variants that influence the trough concentrations of LTG in epilepsy patients following monotherapy regimen (37.5-250 mg/d). Twelve single nucleotide polymorphisms (SNPs) involved in LTG metabolism and transport pathways, including UGT2B7, ABCB1, ABCG2, NR1I2 and HNF4α were genotyped in 140 Chinese epilepsy patients. Steady-state trough concentration of LTG was measured by a high-performance liquid chromatography method. Polymorphisms in ABCG2 rs2231142, rs3114020, HNF4α rs2071197 and ABCB1 rs1128503 were found to be associated with LTG CDR (concentration/dose normalized by body weight). In addition, multiple linear regression analysis revealed that ABCG2 rs2231142 had a remarkable effect on LTG concentrations which is stated to be 4.8% of the variability of LTG and may also help to interpret ethnic difference in LTG pharmacokinetics. Our findings provided new insights that SNPs of genes involved in the transport of LTG contribute to interpatient variation in LTG pharmacokinetics. Future studies are necessary to determine whether these SNPs can be used to provide LTG dosing guidance and influence seizure control and adverse reaction of LTG.
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Yafang
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Xueding
authors.initials: X
authors.lastname: Wang
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pharmacy, Guangdong Provincial Traditional Chinese Medical Hospital, Guangzhou 510080, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Epilepsy Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Ziyi
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Xie
authors.affiliation: Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Jinxin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Jiali
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Neurology, Epilepsy Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. Electronic address: lmzhou56@163.com.
authors.forename: Liemin
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. Electronic address: huangmin@mail.sysu.edu.cn.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D044466:Asian People / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies / Q000379:methods; D005838:Genotype; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics*; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D014227:Triazines / Q000627:therapeutic use*
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D009363:Neoplasm Proteins; D014227:Triazines; D000077213:Lamotrigine
keywords: ABCB1; ABCG2; HNF4α; Lamotrigine; Pharmacogenetics