Effect of the CYP2C19 oxidation polymorphism on fluoxetine metabolism in Chinese healthy subjects.
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.
Liu
Z Q
ZQ
Pharmacogenetics Research Institute, Hunan Medical University, Changsha, Hunan 410078, China.
Cheng
Z N
ZN
Huang
S L
SL
Chen
X P
XP
Ou-Yang
D S
DS
Jiang
C H
CH
Zhou
H H
HH
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*
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