Pharmacokinetics of sertraline in relation to genetic polymorphism of CYP2C19

Objective: Our objective was to evaluate the relationship between the dispo sition of sertraline and the presence of the CYP2C19 gene and to define the contribution of cytochrome P450 2C19 (CYP2C19) to sertraline N-demethylati on. Methods: A single oral 100-mg dose of sertraline was administered to 6 subj ects who were extensive metabolizers and 6 subjects who were poor metaboliz ers recruited from 77 healthy Chinese volunteers whose genotypes were prede termined by polymerase chain reaction-based amplification, followed by rest riction fragment length polymorphism analysis. Phenotypes were determined b y use of the omeprazole metabolic rate. The plasma concentrations of sertra line and desmethylsertraline were determined by gas chromatography with ele ctron-capture detection. Results: Six poor metabolizers with ml mutation had area under the plasma c oncentration versus time curve (AUC(0,infinity) values (983.6 +/- 199.3 mug . h/L versus 697.6 +/- 133.0 mug . h/L; P < .05) and terminal elimination half-life values of sertraline (35.5 +/- 5.6 hours versus 23.5 +/- 4.4 hour s; P < .01) that were significantly higher than the values in 6 extensive m etabolizers who were either homozygous or heterozygous for CYP2CI9*1. The o ral clearance of sertraline in poor metabolizers (105.3 +/- 19.4 L/h) was s ignificantly lower than that of extensive metabolizers (148.4 +/- 28.6 L/h) . The area under the concentration-time curve from 0 to 144 hours and the m aximum plasma concentration of desmethylsertraline in poor metabolizers wer e significantly lower than the values of extensive metabolizers (627.6 +/- 203.8 mug . h/L versus 972.1 +/- 270.3 mug . h/L; P < .05; and 23.6 +/- 6.5 nmol/L versus 32.4 +/- 8.2 nmol/L; P < .01; respectively). Conclusions: The polymorphic CYP2C19 appears to be a major enzyme involved in the N-demethylation of sertraline, and both extensive and poor metaboliz ers had marked differences in the disposition of sertraline.