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).

Aims The present study was designed to define the kinetic behaviour of sertraline N-demethylation in human liver microsomes and to identify the isoforms of cytochrome P450 involved in this metabolic pathway. Methods The kinetics of the formation of N-demethylsertraline were determined in human liver microsomes from six genotyped CYP2C19 extensive (EM) and three poor metabolisers (PM). Selective inhibitors of and specific monoclonal antibodies to various cytochrome P450 isoforms were also employed. Results The kinetics of N-demethylsertraline formation in all EM liver microsomes were fitted by a two-enzyme Michaelis-Menten equation, whereas the kinetics in all PM liver microsomes were best described by a single-enzyme Michaelis-Menten equation similar to the low-aYnity component found in EM microsomes. Mean apparent Km values for the high-and low-aYnity components were 1.9 and 88mm and V max values were 33 and 554 pmol min−1mg 1 protein, respectively, in the EM liver microsomes. Omeprazole (a CYP2C19 substrate) at high concentrations and sulphaphenazole (a selective inhibitor of CYP2C9) substantially inhibited Ndemethylsertraline formation. Of five monoclonal antibodies to various cytochrome P450 forms tested, only anti-CYP2C8/9/19 had any inhibitory eVect on this reaction. The inhibition of sertraline N-demethylation by anti CYP2C8/9/19 was greater in EM livers than in PM livers at both low and high substrate concentrations. However, anti-CYP2C8/9/19 did not abolish the formation of N-demethylsertraline in the microsomes from any of the livers. Conclusions The polymorphic enzyme CYP2C19 catalyses the high-aYnity Ndemethylation of sertraline, while CYP2C9 is one of the low-aYnity componentsof this metabolic pathway.

The study was designed to define the contribution of cytochrome P450 2C19 (CYP2C19) and cytochrome P450 3A4 (CYP3A4) to citalopram N-demethylation and to evaluate the relationship between the disposition of citalopram and CYP2C19 genotype. A single oral 40mg dose of citalopram was administered to eight extensive metabolizers and five poor metabolizers recruited from 77 healthy Chinese volunteers whose genotypes and phenotypes were predetermined. The plasma concentrations of citalopram and desmethylcitalopram were N determined by high-performance liquid chromatography. It was found that the genotype of CYP2C19 had a significant effect on the N-demethylation of citalopram. Poor metabolizers with m1 mutation had higher area under the plasma concentration versus time curve (AUC03) values than did extensive metabolizers. Terminal eliminationelimination half-life (t1/2) values of citalopram in poor metabolizers were significantly higher than the values in extensive metabolizers who were either homozygous or heterozygous with CYP2C19*1. The oral clearance (CLoral) of citalopram in poor metabolizers was significantly lower than that of extensive metabolizers. The AUC03 and maximum plasma concentration (Cmax) of desmethylcitalopram in poor metabolizers were significantly lower than the values of extensive metabolizers. The results show that CYP3A4 is not the major enzyme in the N-demethylation of citalopram among extensive metabolizers. The polymorphism of CYP2C19 plays an important role in the Ndemethylation of citalopram in vivo. The extensive metabolizers and poor metabolizers of CYP2C19 had significant difference in disposition of citalopram in vivo.