title: Effects of the CYP 2D6 genotype and cigarette smoking on the steady-state plasma concentrations of fluvoxamine and its major metabolite fluvoxamino acid in Japanese depressed patients.
abstract: The effects of the cytochrome P450 (CYP) 2D6 genotype and cigarette smoking on the steady-state plasma concentrations (C(ss)) of fluvoxamine (FLV) and its demethylated metabolite fluvoxamino acid (FLA) were studied in 49 Japanese depressed patients receiving FLV 200 mg/d. The C(ss) of FLV and FLA were measured by HPLC, and the wild-type allele (*1) and two mutated alleles causing absent (*5) or decreased (*10) CYP 2D6 activity were identified by PCR methods. The patients were divided into three genotype groups by the number of mutated alleles: 12 cases with no (*1/*1), 27 cases with one (*1/*5 and *1/*10), and 10 cases with two (*5/*10 and *10/*10) mutated alleles. The means +/- SD of the C(ss) of FLV and FLA and the FLA/FLV ratio of all patients were 169.1 +/- 147.5 ng/mL, 83.9 +/- 52.7 ng/mL, and 0.71 +/- 0.50, respectively. The C(ss) of FLV and FLA were not significantly different among the three genotype groups. However, the FLA/FLV ratio was significantly lower in the patients with one (P < 0.05) and two (P < 0.01) mutated alleles than in those with no mutated allele. There was no significant difference between nonsmokers (n = 34) and smokers (n = 15) in these values. In the stepwise multiple regression, the C(ss) of FLA (P < 0.05) and FLA/FLV ratio (P < 0.001) showed significant negative correlations with the number of mutated alleles, and the FLA/FLV ratio was significantly (P < 0.05) lower in women than in men. The present study suggests that the CYP 2D6 genotype and cigarette smoking have no major impact on the C(ss) of FLV and FLA, though CYP 2D6 is involved in the demethylation of FLV.
authors.affiliation: Department of Neuropsychiatry, Yamagata University School of Medicine, Yamagata, Japan.
authors.forename: Gisa
authors.initials: G
authors.lastname: Gerstenberg
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Aoshima
authors.forename: Takashi
authors.initials: T
authors.lastname: Fukasawa
authors.forename: Keizo
authors.initials: K
authors.lastname: Yoshida
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Hisashi
authors.initials: H
authors.lastname: Higuchi
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Murata
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Shimoyama
authors.forename: Tadashi
authors.initials: T
authors.lastname: Ohkubo
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Shimizu
authors.forename: Koichi
authors.initials: K
authors.lastname: Otani
mesh_terms: D000328:Adult; D018687:Antidepressive Agents, Second-Generation / Q000097:blood* / Q000378:metabolism / Q000627:therapeutic use; D044466:Asian People; D002851:Chromatography, High Pressure Liquid; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D003863:Depression / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D016666:Fluvoxamine / Q000097:blood* / Q000378:metabolism / Q000627:therapeutic use; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D012737:Sex Factors; D012907:Smoking
chemical_list: D018687:Antidepressive Agents, Second-Generation; D019389:Cytochrome P-450 CYP2D6; D016666:Fluvoxamine