title: Association between lamotrigine concentrations and ABCB1 polymorphisms in patients with epilepsy.
abstract: BACKGROUND
  Epilepsy is treated with a variety of anticonvulsants that are often used concomitantly. Therefore, therapeutic drug monitoring is often necessary. Along with clinical and environmental factors, genetic predisposition has been recognized to be relevant for interindividual variability in drug response. Polymorphic transporter proteins such as P-glycoprotein significantly influence pharmacokinetics and bioavailability of many structurally unrelated drugs. The aim of the study was to evaluate the impact of polymorphisms in the P-glycoprotein-encoding gene ABCB1 (C1236T, G2677T/A, C3435T) on antiepileptic drug disposition.
  
  
  METHODS
  We recruited 222 patients with epilepsy who were prescribed lamotrigine in monotherapy or polytherapy. Lamotrigine plasma concentrations were analyzed and compared with ABCB1 gene variants. The ABCB1 genotyping was performed by real-time polymerase chain reaction methods. The therapeutic drug monitoring was performed by high-performance liquid chromatography-diode array detector (DAD) and immunoassay.
  
  
  RESULTS
  A significant correlation was confirmed between lamotrigine concentration and additional drugs (P < 0.001). In the whole group, statistical analysis showed correlations between lamotrigine concentrations and ABCB1 C1236T variants: 10.1 and 6.5 μmol/L for CC versus CT + TT, respectively (P = 0.021), and for dose corrected lamotrigine 0.068 and 0.053 μmol·L·mg, for CC versus CT + TT, respectively (P = 0.017). Analysis of a specific haplotype showed that 1236C-2677G-3435C carriers had higher lamotrigine concentrations than 1236T-2677G-3435T carriers (P < 0.001), followed by 1236T-2677T-3435C carriers (P < 0.001).
  
  
  CONCLUSIONS
  ABCB1 C1236T, G2677T/A, C3435T polymorphisms have an influence on lamotrigine serum concentrations.
authors.affiliation: Department of Laboratory Diagnostics, University Hospital Centre Zagreb , Zagreb, Croatia.
authors.forename: Mila
authors.initials: M
authors.lastname: Lovrić
authors.forename: Nada
authors.initials: N
authors.lastname: Božina
authors.forename: Sanja
authors.initials: S
authors.lastname: Hajnšek
authors.forename: Martina Rojnić
authors.initials: MR
authors.lastname: Kuzman
authors.forename: Davor
authors.initials: D
authors.lastname: Sporiš
authors.forename: Zdenka
authors.initials: Z
authors.lastname: Lalić
authors.forename: Tamara
authors.initials: T
authors.lastname: Božina
authors.forename: Paula
authors.initials: P
authors.lastname: Granić
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* / Q000627:therapeutic use; D016903:Drug Monitoring / Q000379:methods; D004827:Epilepsy / Q000097:blood* / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D014227:Triazines / Q000097:blood* / Q000627:therapeutic use
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D014227:Triazines; D000077213:Lamotrigine