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 7.5mg 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: -0.36vs-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.

目的：建立同时测定体外肝微粒体中氟西汀及其代谓十产物去甲氟西汀的反相高效液相色谱紫外检测法。方法：含微粒体蛋白和NADPH发生系统及氟西汀的孵育液加入冰乙腈酸终止反应后，再加入去甲替林作为内标并以，z.正己烷和乙腈的混合液进行萃取，然后以反相ODS柱分离，在226nlTl处以紫外检测器进行检测。结果：孵育体系中没有明显的干扰峰出现，氟西汀和去甲氟西汀洗脱快，分离好，线性范围均为10-800ug/L，最低检测限均为5ug/L，相对回收率为94%-104%，变异系数少于9.1%。结论：本法快速，灵敏，回收率高，且萃取过程简单，可用于体外氟西汀的代谢研究。

AIM: The present study was designed to define the ki-netic behavior of fluoxetine N-demethylation in human liver microsomes and to identify the isoforms of cy-tochrome P-450 (CYP) involved in this metabolic path-way. METHODS: The kinetics of the formation ofnorfluoxetine was determined in human liver microsomes from six genotyped CYP2C19 extensive metabolizers (EM). The correlation studies between the fluoxetine N-demethylase activity and various CYP enzyme activi-ties were performed. Selective inhibitors or chemical probes of various cytochrome P-450 isoforms were also employed. RESULTS: The kinetics of norfluoxetine formation in all liver microsomes were fitted by a single- enzyme Michaelis-Menten equation (mean Km=32umol/L-7umol/L). Significant correlations were found between N-demethylation of fluoxetine at both 25/anol/L and 100 p.mol/L and 3-hydroxylation of tolbu- tamide at 250 panol/L (rl=0.821, P1=0.001; r2=0.668, P2=0.013), respectively, and S-mephenytoin 4'-hydroxylase activity (r=0.717, P=0.006) at high substrate concentration of 100/zmol/L. S-mephenytoin (SMP)(a CC19 substrate) at high concentration and sulfaphenazole (SUL)(a selective inhibitor of CYP2C9) substantially inhibited norfluoxetine formation. The re-action was minimally inhibited by coincubation with chemical probe, inhibitor of CYP3A4 (tfiacetylolean-domycin, TAO). The inhibition of fluoxetine N-demethylation at high substrate concentration (100ptmoL/L) was greater in PM livers than in EM livers (73% vs4, 5%, P<0.01) when the microsomes were precoincu-bated with SUL plus TAO. CONCLUSION: Cy-tochrome P-450 CYP2C9 is likely to be a major CYP iso-form catalyzing fluoxetine N-demethylation in human liv-er microsomes at a substrate concentration close to the therapeutic level, while polymorphic CYP'2C19 may play a more important role in this metabolic pathway at highsubstrate concentration.

Aims: To investigate the incidence of the CYP2C19 polymorphism in the Chinese Dai population. Methods: One hundred and ninety-three healthy Chinese Dai volunteers were identified with respect to CYP2C19 by genotype and phenotype analyses. A polymerase chain reaction-restriction fragment length polymorphism method was performed for genotyping procedures. The 4-hydroxymephenytoin (4-OH-MP) and S/R-mephenytoin (S/R-MP) excreted in the urine were determined by high-performance liquid chromatographyand gas chromatography, respectively. Results: Eighteen subjects were identified as poor metabolisers (PMs). The frequency of PMs in the Chinese Dai subjects was 9.3% (95% confidence interval 5.2, 13.4), which is lowerthan that in the Chinese Han population (P<0.05). Chinese Dai subjects had a higher frequency of the mutant CYP2C19*2 allele (0.303) and a lowerfr equency of the mutant CYP2C19*3 allele (0.034). These two mutant alleles could explain all defi-ciencies of CYP2C19 activity in the Chinese Dai subjects. The frequency of the CYP2C193 allele is significantly lowerthan that in the Chinese Han population (P<0.05). The mean S/R ratio was lower in the homozygous extensive metabolisers (EMs) compared with that in heterozygous EMs (P<0.01), and the latter was lowerthan that in the PMs (P<0.01). Furthermore, the mean S/R ratio in CYP2C193/CYP2C192 heterozygous PMs was possibly lower than that in the CYP2C192/CYP2C19*2 homozygous PMs (P<0.05). Conclusion: The frequencies of PMs and CYP2C19*3 allele in the Chinese Dai population are significantly lowerthan those in the Han population. The CYP2C19genotype analysis is largely consistent with the mephenytoin phenotype analysis. The variability of S/R ratios in EMs and PMs shows a gene-dosage e ect.