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 (40mg) 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

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.

Objective: Our objective was to evaluate the relationship between the disposition of sertraline and the presence of the CYP2C19 gene and to define the contribution of cytochrome P450 2C19 (CYP2C19) to sertraline N-demethylation. Methods: A single oral 100-mg dose of sertraline was administered to 6 subjects who were extensive metabolizers and 6 subjects who were poor metabolizers recruited from 77 healthy Chinese volunteers whose genotypes were predetermined by polymerase chain reaction-based amplification, followed by restriction fragment length polymorphism analysis. Phenotypes were determined by use of the omeprazole metabolic rate. The plasma concentrations of sertraline and desmethylsertraline were determined by gas chromatography with electron-capture detection. Results: Six poor metabolizers with m1 mutation had area under the plasma concentration versus time curve (AUC0-∞) values (983.6±199.3μg·h/L versus 697.6±133.0μg·h/L; P<.05) and terminal elimination half-life values of sertraline (35.5±5.6 hours versus 23.5±4.4 hours; P<.01) that were significantly higher than the values in 6 extensive metabolizers who were either homozygous or heterozygous for CYP2C19*1. The oral clearance of sertraline in poor metabolizers (105.3±19.4L/h) was significantly lower than that of extensive metabolizers (148.4±28.6L/h). The area under the concentration-time curve from 0 to 144 hours and the maximum plasma concentration of desmethylsertraline in poor metabolizers were significantly lower than the values of extensive metabolizers (627.6±203.8μg·h/L versus 972.1±270.3μg·h/L; P<.05; and 23.6±6.5nmol/L versus 32.4±8.2nmol/L; P<.01; respectively).