title: Effect of CYP2B6*6 on Steady-State Serum Concentrations of Bupropion and Hydroxybupropion in Psychiatric Patients: A Study Based on Therapeutic Drug Monitoring Data.
abstract: BACKGROUND
  The clinical effect of bupropion is mediated by its active metabolite hydroxybupropion. Previous studies have reported conflicting impact of the CYP2B6*6 variant allele on the formation of hydroxybupropion from bupropion. The aim of this study was to clarify the effect of CYP2B6*6 and secondarily CYP2D6 genotype on steady-state serum concentrations of bupropion and hydroxybupropion in a large population of psychiatric patients.
  
  
  METHODS
  Retrospective information about dose-adjusted serum concentrations (C/D ratios) of bupropion and hydroxybupropion, CYP2B6 genotype (ie, data on the 2B6*6 polymorphisms 516G>T and 785A>G) and CYP2D6 genotype, was obtained from a therapeutic drug monitoring database (n = 132 patients). C/D ratios of bupropion and hydroxybupropion, and metabolic ratios, were compared between CYP2B6 genotype subgroups by multivariate mixed-model analyses (2B6*1/*1 was defined as control group). In the analyses, CYP2D6 genotype was also included as a covariate.
  
  
  RESULTS
  Homozygous 2B6*6 carriers (n = 7) had significantly lower C/D ratios of hydroxybupropion compared with controls (n = 79), that is, estimated mean 5.8 versus 13.0 nmol·L·mg (P < 0.001). C/D ratio of hydroxybupropion in heterozygous *6 carriers (12.1 nmol·L·mg; n = 46) did not significantly differ compared with controls (P = 0.32). The hydroxybupropion/bupropion metabolic ratios in heterozygous and homozygous 2B6*6 carriers were significantly lower than in controls (P = 0.001 and P < 0.001, respectively). CYP2D6 genotype did not significantly alter the hydroxybupropion C/D ratio, but higher bupropion values were observed in poor versus extensive CYP2D6 metabolizers (P = 0.020).
  
  
  CONCLUSIONS
  This study shows that the CYP2B6*6 variant allele is associated with significantly reduced formation of the active bupropion metabolite in psychiatric patients. Our findings suggest that dose-adjusted serum concentrations of hydroxybupropion at steady state is approximately halved in homozygous CYP2B6*6 carriers, which might imply risk of reduced clinical response in this patient subgroup. The CYP2D6 genotype does not affect hydroxybupropion concentrations and is therefore unlikely to impact bupropion treatment.
authors.affiliation: *Center for Psychopharmacology, Diakonhjemmet Hospital; †Division of Forensic Sciences, Norwegian Institute of Public Health; and ‡Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Norway.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Høiseth
authors.forename: Tore
authors.initials: T
authors.lastname: Haslemo
authors.forename: Linda H
authors.initials: LH
authors.lastname: Uthus
authors.forename: Espen
authors.initials: E
authors.lastname: Molden
mesh_terms: D000328:Adult; D016642:Bupropion / Q000031:analogs & derivatives* / Q000097:blood*; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D016903:Drug Monitoring; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies
chemical_list: C580748:hydroxybupropion; D016642:Bupropion; D065702:Cytochrome P-450 CYP2B6; D019389:Cytochrome P-450 CYP2D6