title: Effect of the CYP2C19 oxidation polymorphism on fluoxetine metabolism in Chinese healthy subjects.
abstract: OBJECTIVE
  The study was designed to investigate whether genetically determined CYP2C19 activity affects the metabolism of fluoxetine in healthy subjects.
  
  
  METHODS
  A single oral dose of fluoxetine (40 mg) was administrated successively to 14 healthy young men with high (extensive metabolizers, n=8) and low (poor metabolizers, n = 6) CYP2C19 activity. Blood samples were collected for 5-7 half-lives and fluoxetine, and norfluoxetine were determined by reversed-phase high performance liquid chromatography.
  
  
  RESULTS
  Poor metabolizers (PMs) showed a mean 46% increase in fluoxetine peak plasma concentrations (Cmax, P < 0.001), 128% increase in area under the concentration vs time curve (AUC(0, infinity), P < 0.001), 113% increase in terminal elimination half-life (t(1/2)) (P < 0.001), and 55% decrease in CLo (P < 0.001) compared with extensive metabolizers (EMs). Mean +/- (s.d) norfluoxetine AUC(0, 192 h) was significantly lower in PMs than that in EMs (1343 +/- 277 vs 2935 +/- 311, P < 0.001). Mean fluoxetine Cmax and AUC(0, infinity) in wild-type homozygotes (CYP2C19*1/CYP2C19*1) were significantly lower than that in PMs (22.4 +/- 3.9 vs 36.7 +/- 8.9, P < 0.001; 732 +/- 42 vs 2152 +/- 492, P < 0.001, respectively). Mean oral clearance in individuals with the wild type homozygous genotype was significantly higher than that in heterozygotes and that in PMs (54.7 +/- 3.4 vs 36.0 +/- 8.7, P < 0.01; 54.7 +/- 3.4 vs 20.6 +/- 6.2, P < 0.001, respectively). Mean norfluoxetine AUC(0, 192 h) in PMs was significantly lower than that in wild type homozygotes (1343 +/- 277 vs 3163 +/- 121, P < 0.05) and that in heterozygotes (1343 +/- 277 vs 2706 +/- 273, P < 0.001), respectively.
  
  
  CONCLUSIONS
  The results indicated that CYP2C19 appears to play a major role in the metabolism of fluoxetine, and in particular its N-demethylation among Chinese healthy subjects.
authors.affiliation: Pharmacogenetics Research Institute, Hunan Medical University, Changsha, Hunan 410078, China.
authors.forename: Z Q
authors.initials: ZQ
authors.lastname: Liu
authors.forename: Z N
authors.initials: ZN
authors.lastname: Cheng
authors.forename: S L
authors.initials: SL
authors.lastname: Huang
authors.forename: X P
authors.initials: XP
authors.lastname: Chen
authors.forename: D S
authors.initials: DS
authors.lastname: Ou-Yang
authors.forename: C H
authors.initials: CH
authors.lastname: Jiang
authors.forename: H H
authors.initials: HH
authors.lastname: Zhou
mesh_terms: D000293:Adolescent; D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases; D001711:Biotransformation; D002681:China / Q000453:epidemiology; D002851:Chromatography, High Pressure Liquid; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D018628:Gene Dosage; D005838:Genotype; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010084:Oxidation-Reduction; D011110:Polymorphism, Genetic; D017367:Selective Serotonin Reuptake Inhibitors / Q000493:pharmacokinetics*
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System; D005473:Fluoxetine; D006899:Mixed Function Oxygenases; D017367:Selective Serotonin Reuptake Inhibitors; C045793:CYP2C19 protein, human; C036139:norfluoxetine