title: Impact of genetic variability in CYP2D6, CYP3A5, and ABCB1 on serum concentrations of quetiapine and N-desalkylquetiapine in psychiatric patients.
abstract: BACKGROUND
  To investigate the impact of genetic variability in CYP2D6, CYP3A5, and ABCB1 on steady-state serum concentrations of quetiapine and the active metabolite, N-desalkylquetiapine, in psychiatric patients.
  
  
  METHODS
  Measured serum concentrations of quetiapine and N-desalkylquetiapine from patients with biobanked DNA samples were included retrospectively from a routine therapeutic drug monitoring database. The impact of CYP2D6, CYP3A5, and ABCB1 (345C>T) genotypes on dose-adjusted serum concentrations (C/D ratios) of quetiapine and N-desalkylquetiapine was investigated by multivariate mixed model analysis.
  
  
  RESULTS
  In total, 289 patients with 633 serum measurements were included. In the multivariate analysis, mean C/D ratio of N-desalkylquetiapine was estimated to be 33% and 22% higher in inherent CYP2D6 poor metabolizers (P = 0.03) and heterozygous extensive metabolizers (P < 0.001), respectively, compared with inherent extensive metabolizers. The ABCB1 3435C>T polymorphism and CYP3A5 genotype had no significant influence on either of the substances in the present material.
  
  
  CONCLUSIONS
  Genetic variability in CYP2D6 contributes to the interindividual variability in steady-state serum concentrations of N-desalkylquetiapine. Although the metabolite exhibits relevant pharmacological activity, the quantitative effect of CYP2D6 genotype on serum concentration of N-desalkylquetiapine is probably of limited clinical relevance for quetiapine treatment.
authors.affiliation: *Center for Psychopharmacology, Diakonhjemmet Hospital; and †Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Norway.
authors.forename: Gry V
authors.initials: GV
authors.lastname: Bakken
authors.forename: Espen
authors.initials: E
authors.lastname: Molden
authors.forename: Monica
authors.initials: M
authors.lastname: Hermann
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014150:Antipsychotic Agents / Q000493:pharmacokinetics; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D001523:Mental Disorders / Q000188:drug therapy; D008875:Middle Aged; D015999:Multivariate Analysis; D011110:Polymorphism, Genetic; D000069348:Quetiapine Fumarate / Q000493:pharmacokinetics*; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D014150:Antipsychotic Agents; D000069348:Quetiapine Fumarate; C510164:CYP3A5 protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A