title: Pharmacogenetics and Treatment Response in Narcolepsy Type 1: Relevance of the Polymorphisms of the Drug Transporter Gene ABCB1.
abstract: OBJECTIVE
  Narcolepsy type 1 (NT1) is a chronic hypersomnia clinically characterized by daytime sleepiness and cataplexy. Narcolepsy type 1 treatments target individual symptoms: wake-promoting agents (eg, modafinil) are effective for sleepiness, antidepressants (eg, venlafaxine) on cataplexy, whereas sodium oxybate on both. Narcolepsy type 1 patients variably respond to modafinil and venlafaxine independently of individual clinical features.Given the potential influence of drug transmembrane transport (glycoprotein-P) on drug response, we explored the relation between genetic polymorphisms in the ABCB1 gene and clinical response to modafinil/venlafaxine in NT1.
  
  
  METHODS
  Individual drug response and genotypes were assessed in 107 NT1 patients (males/females, 64/43; mean age, 38 ± 21 years) treated with modafinil and/or venlafaxine at stable doses for at least 3 months. Minisequencing was performed to detect single-nucleotide polymorphisms in ABCB1. Patients with different responses to treatment were contrasted by Fisher exact test and multivariate analysis.
  
  
  RESULTS
  The ABCB1 diplotype was significantly associated with clinical response to modafinil, with the CGC-TTT (1236/2677/3435) being more frequent in the modafinil responder versus nonresponder group (P = 0.013). Conversely, no significant associations with clinical response to venlafaxine were found.
  
  
  CONCLUSIONS
  The ABCB1 variants modulate therapeutic response to modafinil and may partly explain pharmacoresistance in NT1 patients.
authors.affiliation: *Departments of Biomedical and Neuromotor Sciences (DIBINEM) and †Medical and Surgical Sciences (DIMES), University of Bologna; and ‡IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Moresco
authors.forename: Laura Natalia
authors.initials: LN
authors.lastname: Riccardi
authors.forename: Fabio
authors.initials: F
authors.lastname: Pizza
authors.forename: Corrado
authors.initials: C
authors.lastname: Zenesini
authors.forename: Leonardo
authors.initials: L
authors.lastname: Caporali
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Plazzi
authors.forename: Susi
authors.initials: S
authors.lastname: Pelotti
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000328:Adult; D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use*; D001559:Benzhydryl Compounds / Q000627:therapeutic use*; D065701:Cytochrome P-450 CYP3A Inducers / Q000627:therapeutic use*; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077408:Modafinil; D009290:Narcolepsy / Q000188:drug therapy* / Q000235:genetics; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012720:Severity of Illness Index; D000069470:Venlafaxine Hydrochloride / Q000627:therapeutic use*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D018687:Antidepressive Agents, Second-Generation; D001559:Benzhydryl Compounds; D065701:Cytochrome P-450 CYP3A Inducers; D000069470:Venlafaxine Hydrochloride; D000077408:Modafinil