title: Association of polymorphisms in EPHX1, UGT2B7, ABCB1, ABCC2, SCN1A and SCN2A genes with carbamazepine therapy optimization.
abstract: OBJECTIVE
  Carbamazepine (CBZ) is one of the most widely used antiepileptic drugs. The aim of the present study is to investigate the impacts of polymorphisms in genes related to pharmacokinetic and pharmacodynamic pathways of CBZ on the large interindividual variability in dosages and concentrations.
  
  
  RESULTS
  Genetic polymorphisms in the candidate genes were detected in 234 epileptic patients under maintenance CBZ monotherapy by real-time PCR and PCR-RFLP. Results of statistical analysis demonstrated that carriers of the variant SCN1A IVS5-91G>A and EPHX1 c.337T>C allele tended to require higher CBZ dosages and lower ln(concentration-dose ratios) than noncarriers (p < 0.0001) and the homozygous carriers also seemed to require higher CBZ dosages and lower ln(concentration-dose ratios) (p < 0.0001). In addition, the multiple regression model of concentration-dose ratio of CBZ also revealed that genetic variants in SCN1A, EPHX1 and UGT2B7 genes interactively affect the concentration-dose ratio of CBZ (adjusted r(2) = 55%).
  
  
  CONCLUSIONS
  The present study identified genetic factors associated with CBZ therapy optimization and provided useful information for individualized CBZ therapy in epileptic patients. Further studies in larger populations are needed to confirm our results.
authors.affiliation: Department of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan.
authors.forename: Chin-Chuan
authors.initials: CC
authors.lastname: Hung
authors.forename: Wei-Lun
authors.initials: WL
authors.lastname: Chang
authors.forename: Jia-Ling
authors.initials: JL
authors.lastname: Ho
authors.forename: John Jen
authors.initials: JJ
authors.lastname: Tai
authors.forename: Tsung-Jen
authors.initials: TJ
authors.lastname: Hsieh
authors.forename: Hsiao-Ching
authors.initials: HC
authors.lastname: Huang
authors.forename: Yow-Wen
authors.initials: YW
authors.lastname: Hsieh
authors.forename: Horng-Huei
authors.initials: HH
authors.lastname: Liou
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics*; D002220:Carbamazepine / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D004851:Epoxide Hydrolases / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D014453:Glucuronosyltransferase / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D062550:NAV1.1 Voltage-Gated Sodium Channel; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D002220:Carbamazepine; D004851:Epoxide Hydrolases; D014453:Glucuronosyltransferase; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D062550:NAV1.1 Voltage-Gated Sodium Channel; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D015222:Sodium Channels; C513055:ABCB1 protein, human; C000715087:ABCC2 protein, human; C568242:SCN1A protein, human; C568251:SCN2A protein, human; C491474:UGT2B7 protein, human; C522330:EPHX1 protein, human