title: Association of ABCB1 C3435T polymorphism with phenobarbital resistance in Thai patients with epilepsy.
abstract: OBJECTIVE
  One-third of patients with epilepsy are resistant to anti-epileptic drugs (AEDs). Drug-resistant epilepsy is believed to be multifactorial involving both genetic and non-genetic factors. Genetic variations in the ABCB1 gene encoding the drug efflux transporter, p-glycoprotein (p-gp), may influence the interindividual variability in AED response by limiting drugs from reaching their target. Phenobarbital (PB), one of the most cost-effective and widely used AEDs in developing countries, has been reported to be transported by p-gp. This study aimed to investigate the association of a genetic variant, ABCB1 3435C>T, and non-genetic factors with phenobarbital response in Thai patients with epilepsy.
  
  
  METHODS
  One hundred and ten Thai patients with epilepsy who were treated with PB maintenance doses were enrolled in this study. Two phenotypic groups, PB-responsive epilepsy and PB-resistant epilepsy, were defined according to the International League Against Epilepsy (ILAE) criteria. Subjects were genotyped for ABCB1 3435C>T (rs1045642). Multiple logistic regression analysis was tested for the association of ABCB1 3435C>T polymorphism and non-genetic factors with PB response.
  
  
  CONCLUSIONS
  Sixty-two PB-responsive epilepsy subjects and 48 PB-resistant epilepsy subjects were identified. All genotype frequencies of the ABCB1 3435C>T SNP were consistent with the Hardy-Weinberg equilibrium (P > 0·05). The ABCB1 3435C>T polymorphism and type of epilepsy were associated with response to PB. Patients with PB-resistant epilepsy had a significantly higher frequency of ABCB1 3435CC genotype and had focal epilepsy more often than patients with PB-responsive epilepsy (adjusted OR = 3·962, 95% CI = 1·075-14·610, P-value = 0·039; adjusted OR = 5·936, 95% CI = 2·272-15·513, P-value < 0·001, respectively). The model explained 25·5% of the variability in response to PB (R(2)  = 0·255).
  
  
  CONCLUSIONS
  Thai patients of ABCB1 3435CC genotype and with focal epilepsy were more often PB resistant. Those two factors partly account for the variability in Thai epilepsy patients' response to phenobarbital.
authors.affiliation: Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand.
authors.forename: T
authors.initials: T
authors.lastname: Keangpraphun
authors.forename: S
authors.initials: S
authors.lastname: Towanabut
authors.forename: Y
authors.initials: Y
authors.lastname: Chinvarun
authors.forename: P
authors.initials: P
authors.lastname: Kijsanayotin
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000494:pharmacology*; D044466:Asian People / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D010634:Phenobarbital / Q000493:pharmacokinetics / Q000494:pharmacology*; D020641:Polymorphism, Single Nucleotide; D013785:Thailand
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D010634:Phenobarbital
keywords: ABCB1 C3435T; Thai patients with epilepsy; phenobarbital; polymorphism; resistance