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Aims To investigate the distribution of CYP3A activity in the Chinese population, and to test for gender-related differences in CYP3A activity. Methods Using midazolam as a probe drug, CYP3A activity in 202 Chinese healthy subjects (104 men) was measured by plasma 1′-hydroxymidazolam:midazolam (1′-OH-MDZ:MDZ) ratio at 1 h after oral administration of 7.5 mg midazolam. The different phases of the menstrual cycle including preovulatory, ovulatory and luteal phases of 66 women phenotyped with midazolam were recorded. The concentrations of 1′-OH-MDZ and MDZ in plasma were measured by HPLC Results A 13-fold variation of CYP3A activity (log1′-OH-MDZ:MDZ: range -0.949–0.203) was shown. The CYP3A activity was normally distributed as indicated by the frequency distribution histogram, the probit plot and the Kolmogorov–Smirnov test (P > 0.05). The CYP3A activity of women was higher than that of men (median: -0.36 vs -0.43, P < 0.05; 95% CI for difference: -0.127, -0.012). There was a significant difference in CYP3A activity between the three phases of the menstrual cycle. The activity was highest in the preovulatory phase and decreased sequentially in the ovulatory and luteal phases (P < 0.05). Conclusions A normal distribution of CYP3A activity was observed in the Chinese population. The CYP3A activity is higher in female subjects than in males. CYP3A activity differed across the phases of the menstrual cycle. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]