title: CYP2D6 genotype and smoking influence fluvoxamine steady-state concentration in Japanese psychiatric patients: lessons for genotype-phenotype association study design in translational pharmacogenetics.
abstract: The CYP2D6 enzyme is a capacity-limited high-affinity drug elimination pathway that metabolizes numerous psychiatric medicines. The capacity-limited nature of this enzyme suggests that drug dose may serve as an important factor that influence genotype-phenotype associations. However, dose dependency of CYP2D6 genotype contributions to drug elimination, and its interaction with environmental factors (e.g., smoking) did not receive adequate attention in translational study designs. Fluvoxamine is a selective serotonin reuptake inhibitor antidepressant. Fluvoxamine concentration is one of the factors previously linked to clinical remission in moderate to severe depression. We investigated the joint effect of smoking (an inducer of CYP1A2) and CYP2D6 genotype on interindividual variability in fluvoxamine steady-state concentration. Fluvoxamine concentration was measured in 87 patients treated with 50, 100, 150 or 200 mg/d. While CYP2D6 genotype significantly influenced fluvoxamine concentration in all four dose groups (p < 0.05), the percentage variance explained (R²) by CYP2D6 decreased as the dose of fluvoxamine increased. Smoking status (nonsmokers vs. smoking 20 or more cigarettes/d) significantly affected fluvoxamine concentration in the 50 mg/d group only (p = 0.005). Together, CYP2D6 genotype and smoking status explained 23% of the variance in fluvoxamine concentration but only at the low 50 mg/d dose group. These findings contribute to evidence-based and personalized choice of fluvoxamine dose using smoking status and CYP2D6 genetic variation. Additionally, these data lend evidence for drug dose as an important variable in translational pharmacogenetic study design and pharmaceutical phenotype associations with capacity-limited drug metabolism pathways such as CYP2D6.
authors.affiliation: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Yutaro
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Takuro
authors.initials: T
authors.lastname: Sugai
authors.forename: Naoki
authors.initials: N
authors.lastname: Fukui
authors.forename: Junzo
authors.initials: J
authors.lastname: Watanabe
authors.forename: Shin
authors.initials: S
authors.lastname: Ono
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Inoue
authors.forename: Vural
authors.initials: V
authors.lastname: Ozdemir
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Someya
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics*; D016009:Chi-Square Distribution; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D016666:Fluvoxamine / Q000097:blood / Q000493:pharmacokinetics*; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007564:Japan; D008297:Male; D001523:Mental Disorders / Q000188:drug therapy* / Q000201:enzymology / Q000208:ethnology / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D018579:Patient Selection; D010597:Pharmacogenetics; D010641:Phenotype; D012044:Regression Analysis; D017367:Selective Serotonin Reuptake Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D012907:Smoking / Q000208:ethnology* / Q000378:metabolism*; D057170:Translational Research, Biomedical
chemical_list: D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6; D016666:Fluvoxamine; D017367:Selective Serotonin Reuptake Inhibitors; C504573:CYP1A2 protein, human