title: Effects of UGT1A9 genetic polymorphisms on monohydroxylated derivative of oxcarbazepine concentrations and oxcarbazepine monotherapeutic efficacy in Chinese patients with epilepsy.
abstract: OBJECTIVE
  The human UDP-glucuronosyltransferase which is genetically polymorphic catalyzes glucuronidations of various drugs. The interactions among UGT1A4, UGT1A6, UGT1A9, and UGT2B15 genetic polymorphisms, monohydroxylated derivative (MHD) of oxcarbazepine (OXC) plasma concentrations, and OXC monotherapeutic efficacy were explored in 124 Chinese patients with epilepsy receiving OXC monotherapy.
  
  
  METHODS
  MHD is the major active metabolite of OXC, and its plasma concentration was measured using high-performance liquid chromatography when patients reached their maintenance dose of OXC. Genomic DNA was extracted from whole blood and SNP genotyping performed using PCR followed by dideoxy chain termination sequencing. We followed the patients for at least 1 year to evaluate the OXC monotherapy efficacy. Patients were divided into two groups according to their therapeutic outcome: group 1, seizure free; group 2, not seizure free. The data were analyzed using T test, one-way analysis of variance (ANOVA), Kruskal-Wallis test, chi-square test, Fisher's exact test, correlation analysis, and multivariate regression analysis.
  
  
  RESULTS
  T test analysis showed that MHD plasma concentrations were significantly different between the two groups (p = 0.002). One-way ANOVA followed by Bonferroni post hoc testing of four candidate SNPs revealed that carriers of the UGT1A9 variant allele I399 C > T (TT 13.28 ± 7.44 mg/L, TC 16.41 ± 6.53 mg/L) had significantly lower MHD plasma concentrations and poorer seizure control than noncarriers (CC 22.24 ± 8.49 mg/L, p < 0.05).
  
  
  CONCLUSIONS
  In our study, we have demonstrated the effects of UGT1A9 genetic polymorphisms on MHD plasma concentrations and OXC therapeutic efficacy. Through MHD monitoring, we can predict OXC therapeutic efficacy, which may be useful for the personalization of OXC therapy in epileptic patients.
authors.affiliation: Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Youxin
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China. drxunyiwu@vip.163.com.
authors.forename: Xunyi
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China. chunlaima@126.com.
authors.forename: Chunlai
authors.initials: C
authors.lastname: Ma
authors.affiliation: Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Xu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002220:Carbamazepine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D002648:Child; D002681:China; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D006900:Hydroxylation; D008297:Male; D008875:Middle Aged; D000078330:Oxcarbazepine; D020641:Polymorphism, Single Nucleotide; D000090264:UDP-Glucuronosyltransferase 1A9; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; C000715591:UGT1A9 protein, human; D002220:Carbamazepine; D014453:Glucuronosyltransferase; D000090264:UDP-Glucuronosyltransferase 1A9; D000078330:Oxcarbazepine
keywords: Epilepsy; Genetic polymorphism; MHD; Oxcarbazepine; Therapeutic efficacy; UGT1A9