Effect of the CYP2C19 oxidation polymorphism on fluoxetine metabolism in Chinese healthy subjects

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Abstract
Aims  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,∞), P < 0.001), 113% increase in terminal elimination half‐life (t½) (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,∞) 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.