title: Polymorphic Variants of SCN1A and EPHX1 Influence Plasma Carbamazepine Concentration, Metabolism and Pharmacoresistance in a Population of Kosovar Albanian Epileptic Patients.
abstract: OBJECTIVE
  The present study aimed to evaluate the effects of gene variants in key genes influencing pharmacokinetic and pharmacodynamic of carbamazepine (CBZ) on the response in patients with epilepsy.
  
  
  METHODS
  Five SNPs in two candidate genes influencing CBZ transport and metabolism, namely ABCB1 or EPHX1, and CBZ response SCN1A (sodium channel) were genotyped in 145 epileptic patients treated with CBZ as monotherapy and 100 age and sex matched healthy controls. Plasma concentrations of CBZ, carbamazepine-10,11-epoxide (CBZE) and carbamazepine-10,11-trans dihydrodiol (CBZD) were determined by HPLC-UV-DAD and adjusted for CBZ dosage/kg of body weight.
  
  
  RESULTS
  The presence of the SCN1A IVS5-91G>A variant allele is associated with increased epilepsy susceptibility. Furthermore, carriers of the SCN1A IVS5-91G>A variant or of EPHX1 c.337T>C variant presented significantly lower levels of plasma CBZ compared to carriers of the common alleles (0.71 ± 0.28 vs 1.11±0.69 μg/mL per mg/Kg for SCN1A IVS5-91 AA vs GG and 0.76 ± 0.16 vs 0.94 ± 0.49 μg/mL per mg/Kg for EPHX1 c.337 CC vs TT; P<0.05 for both). Carriers of the EPHX1 c.416A>G showed a reduced microsomal epoxide hydrolase activity as reflected by a significantly decreased ratio of CBZD to CBZ (0.13 ± 0.08 to 0.26 ± 0.17, p<0.05) also of CBZD to CBZE (1.74 ± 1.06 to 3.08 ± 2.90; P<0.05) and CDRCBZD (0.13 ± 0.08 vs 0.24 ± 0.19 μg/mL per mg/Kg; P<0.05). ABCB1 3455C>T SNP and SCN1A 3148A>G variants were not associated with significant changes in CBZ pharmacokinetic. Patients resistant to CBZ treatment showed increased dosage of CBZ (657 ± 285 vs 489 ± 231 mg/day; P<0.001) but also increased plasma levels of CBZ (9.84 ± 4.37 vs 7.41 ± 3.43 μg/mL; P<0.001) compared to patients responsive to CBZ treatment. CBZ resistance was not related to any of the SNPs investigated.
  
  
  CONCLUSIONS
  The SCN1A IVS5-91G>A SNP is associated with susceptibility to epilepsy. SNPs in EPHX1 gene are influencing CBZ metabolism and disposition. CBZ plasma levels are not an indicator of resistance to the therapy.
authors.affiliation: Department of Pharmacy, Faculty of Medicine, University of Prishtina, Prishtina, Kosovo.|Institute of Pharmacology and Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Prishtina, Prishtina, Kosovo.|Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.
authors.forename: Armond
authors.initials: A
authors.lastname: Daci
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano, Milan, Italy.
authors.forename: Giangiacomo
authors.initials: G
authors.lastname: Beretta
authors.affiliation: University of Lincoln, School of Pharmacy, Joseph Banks Laboratories, Green Lane, Lincoln, LN6 7DL, United Kingdom.
authors.forename: Driton
authors.initials: D
authors.lastname: Vllasaliu
authors.affiliation: Department of Pharmacy, Faculty of Medicine, University of Prishtina, Prishtina, Kosovo.
authors.forename: Aida
authors.initials: A
authors.lastname: Shala
authors.affiliation: Neurology Clinic, University Clinical Center of Kosova, Prishtina, Kosovo.
authors.forename: Valbona
authors.initials: V
authors.lastname: Govori
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.|Center for the Study of Atherosclerosis, Ospedale Bassini, Cinisello Balsamo, Italy.
authors.forename: Giuseppe Danilo
authors.initials: GD
authors.lastname: Norata
authors.affiliation: Institute of Pharmacology and Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Prishtina, Prishtina, Kosovo.
authors.forename: Shaip
authors.initials: S
authors.lastname: Krasniqi
mesh_terms: D000293:Adolescent; D000328:Adult; D000415:Albania; D000927:Anticonvulsants / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002220:Carbamazepine / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D004827:Epilepsy / Q000188:drug therapy*; D004851:Epoxide Hydrolases / Q000235:genetics*; D005006:Ethnicity / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D013056:Spectrophotometry, Ultraviolet; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D062550:NAV1.1 Voltage-Gated Sodium Channel; C568242:SCN1A protein, human; D002220:Carbamazepine; D004851:Epoxide Hydrolases; C522330:EPHX1 protein, human