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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 40-mg 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 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 (AUC0--> infinity ) values than did extensive metabolizers. Terminal elimination 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 AUC0--> infinity 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 N- demethylation of citalopram in vivo. The extensive metabolizers and poor metabolizers of CYP2C19 had significant difference in disposition of citalopram in vivo.

This work evaluated the kinetic behavior of fluoxetine O-dealkylation in human liver microsomes from different CYP2C19 genotypes and identified the isoenzymes of cytochrome P450 involved in this metabolic pathway. The kinetics of the rho-trifluoromethylphenol (TFMP) formation from fluoxetine was determined in human liver microsomes from three homozygous (wt/wt) and three heterozygous (wt/m1) extensive metabolizers (EMs) and three poor metabolizers (PMs) with m1 mutation (m1/m1) with respect to CYP2C19. The formation rate of TFMP was determined by gas chromatograph with electron-capture detection. The kinetics of TFMP formation was best described by the two-enzyme and single-enzyme Michaelis-Menten equation for liver microsomes from CYP2C19 EMs and PMs, respectively. The mean intrinsic clearance (V(max)/K(m)) for the high- and low-affinity component was 25.2 microl/min/nmol and 3.8 microl/min/nmol of cytochrome P450 in the homozygous EMs microsomes and 12.8 microl/min/nmol and 2.9 microl/min/nmol of cytochrome P450 in the heterozygous EMs microsomes, respectively. Omeprazole (a CYP2C19 substrate) at a high concentration and triacetyloleandomycin (a selective inhibitor of CYP3A4) substantially inhibited O-dealkylation of fluoxetine. Furthermore, fluoxetine O-dealkylation was correlated significantly with S-mephenytoin 4'-hydroxylation at a low substrate concentration and midazolam 1'-hydroxylation at a high substrate concentration in liver microsomes of 11 Chinese individuals, respectively. Moreover, there were obvious differences in the O-dealkylation of fluoxetine in liver microsomes from different CYP2C19 genotypes and in microsomal fractions of different human-expressed lymphoblast P450s. The results demonstrated that polymorphic CYP2C19 and CYP3A4 enzymes were the major cytochrome P450 isoforms responsible for fluoxetine O-dealkylation, whereas CYP2C19 catalyzed the high-affinity O-dealkylation of fluoxetine, and its contribution to this metabolic reaction was gene dose-dependent.