Pharmacokinetics of sertraline in relation togenetic polymorphism of CYP2C19 Objective: Our objective was to evaluate the relationship between the disposition of sertraline and the pres-
ence of the CYP2C19
gene and to define the contribution of cytochrome P450 2C19 (CYP2C19) to ser-
traline N
A single oral 100-mg dose of sertraline was administered to 6 subjects who were extensive metab-
olizers 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 chromatog-
raphy with electron-capture detection.
Six poor metabolizers with m1 mutation had area under the plasma concentration versus time
curve (AUC0-
) values (983.6 ± 199.3 µg · h/L versus 697.6 ± 133.0 µg · 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 sig-
nificantly higher than the values in 6 extensive metabolizers who were either homozygous or heterozy-
gous for CYP2C19*1
. The oral clearance of sertraline in poor metabolizers (105.3 ± 19.4 L/h) was sig-
nificantly lower than that of extensive metabolizers (148.4 ± 28.6 L/h). The area under the concentra-
tion-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 ± 203.8
µg ·
h/L versus 972.1 ± 270.3
µg · h/L; P < .05; and 23.6 ± 6.5 nmol/L versus 32.4 ± 8.2 nmol/L; P < .01;
The polymorphic CYP2C19 appears to be a major enzyme involved in the N-demethylation
of sertraline, and both extensive and poor metabolizers had marked differences in the disposition of ser-
traline. (Clin Pharmacol Ther 2001;70:42-7.)

Jiu-Hui Wang, MD, Zhao-Qian Liu, MD, PhD, Wei Wang, MS, Xiao-Ping Chen, MS,
Yan Shu, MD, PhD, Nan He, MS, and Hong-Hao Zhou, MD
Changsha, Hunan, China
Sertraline is a potent and selective serotonin reup- 0.2% of unchanged drug appears in urine within 48 take inhibitor in the central nervous system and is hours of administration. Desmethylsertraline is the pri- widely used to treat depression and obsessive-compul- mary metabolite of sertraline, which is considered to sive behavior.1,2 It is extensively metabolized by the hepatic cytochrome P450 (CYP) enzymes, and less than Some in vitro studies have shown that the formation of desmethylsertraline was catalyzed by multiple iso- From the Pharmacogenetics Research Institute, Hunan Medical Uni- forms of CYP in human liver microsomes, including Supported by China Medical Board grants 92-568 and 99-697.
CYP3A4.4,5 Nevertheless, there is some confusion as Received for publication Jan 11, 2001; accepted April 15, 2001.
to which CYP isoforms are responsible for the N- Reprint requests: Hong-Hao Zhou, Professor, Pharmacogenetics Research Institute, Hunan Medical University, Changsha, Hunan demethylation of sertraline. Recently, Kobayashi et al4 reported that at least 5 CYP isoforms are involved in the N-demethylation of sertraline and that the contri- Copyright 2001 by the American Society for Clinical Pharmacology bution of CYP2D6 is the most important among the 5 isoforms, but contribution of any individual isoform 13/1/116513
does not exceed 40% of overall metabolism. However, CLINICAL PHARMACOLOGY & THERAPEUTICSVOLUME 70, NUMBER 1 our recent in vitro study found that CYP2D6 and examination, and laboratory screening tests. No med- CYP3A4 appear not to be involved in the N-demethyl- ication or ethanol consumption was allowed for at least ation of sertraline and that CYP2C19 is probably a 2 weeks before the clinical study. The Ethics Commit- major enzyme contributing to the N-demethylation of tees of Hunan Medical University approved the study, sertraline because of its high affinity for sertraline and and written informed consent was obtained from all the marked difference in the enzyme kinetics of sertra- line N-demethylation between human liver microsomes Determination of CYP2C19 genotypes and pheno-
from different CYP2C19 genotypes.5 Previously, there types. All subjects belonged to a pool of volunteers with
has been little direct evidence regarding the specific predetermined CYP2C19 genotypes. CYP2C19*2 (m1) CYP isoform that mediates the N-demethylation of ser- and CYP2C19*3 (m2) mutations were determined by traline in vivo, except that Hamelin et al6 reported no conventional restriction fragment length polymorphism effect of CYP2D6 activity in vivo on sertraline or and polymerase chain reaction.7,8 CYP2C19 pheno- desmethylsertraline pharmacokinetics.
types were determined with the use of omeprazole as a Interindividual and ethnic differences in drug metab- probe drug.14 In brief, 12 subjects whose genotypes olism and response are a clinically important problem were known were given a single oral 20-mg dose of in the use of many drugs. A major cause of problems omeprazole (Astra Pharmaceutical Production AB, is the variability of activity of drug-metabolizing Södertälje, Sweden). The concentrations of omeprazole enzymes in the liver. CYP2C19 is a clinically impor- and its 5-hydroxymetabolite were measured in plasma tant enzyme because of its genetic polymorphism that 2 hours after oral administration of omeprazole, and log separates subjects into two different phenotypes— omeprazole hydroxylation indices (Log10 [Omepra- extensive and poor metabolizers of S-mephenytoin.
zole]/[5-Hydroxyomeprazole]) were calculated. An CYP2C19 activity is genetically determined, and its index of a log10 metabolic ratio <1 was taken to corre- genetic polymorphism shows marked interracial differ- spond to an extensive metabolizer phenotype, whereas ences. The incidence of the poor metabolizer pheno- an index of ≥1 corresponded to a poor metabolizer phe- type is markedly higher in Asian populations (13%- 23%) than in white populations (2%-5%).7 The normal Collection of samples. After an overnight fast, all
allele and 5 defective alleles of CYP2C19 have been subjects received a single oral dose of 100 mg sertra- designated as CYP2C19*1 (wild type), CYP2C19*2 line (Pfizer Co, Dalian, China) with 200 mL water. Sub- jects were allowed to receive food and drink for 2 hours CYP2C19*5 (m4), and CYP2C19*6 (m5).7-11 The com- after drug administration. Then 8-mL venous blood binations of CYP2C19*2 and CYP2C19*3 may account samples were collected into heparinized tubes immedi- for 100% of Asian poor metabolizers, whereas all of ately (0 hours) and at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, the genetic defects are found in white subjects.7-11 36, 48, 72, 96, 120, and 144 hours after administration There is large interindividual variability in the dis- of the drug. Plasma was obtained and kept frozen at position and response of sertraline.3,12,13 This study was undertaken to evaluate the contribution of CYP2C19 to Plasma sertraline and desmethylsertraline assay.
the N-demethylation of sertraline and to investigate the The plasma concentrations of sertraline and relationship between the disposition of sertraline and desmethylsertraline were determined by a minor modi- the genetic polymorphism of CYP2C19.
fied gas chromatography with electron-capture detec-tion.15 One-step extraction was used in the study.
Diazepam was used as the internal standard. In brief, Subjects. Before the full pharmacokinetic study of
we added 0.2 mL diazepam (45.7 µmol/L) to 1 mL of sertraline, 77 unrelated healthy Chinese volunteers the plasma samples that contained sertraline and were screened for their CYP2C19 genotypes. Six exten- desmethylsertraline, and we adjusted the solution to pH sive metabolizers genotyped as CYP2C19*1/*1, >10.5 with sodium hydroxide (1.0 mol/L) and then CYP2C19*1/*2, or CYP2C19*1/CYP2C*3 and 6 poor extracted with diethylether/hexane (80:20 [vol/vol]).
metabolizers genotyped as CYP2C19*2/*2 The organ phase was transferred to another clean glass CYP2C19*2/*3 were randomly selected for participa- tube and evaporated to a volume of about 200 µL at tion in the study. The mean age was 20 ± 1 years (range, room temperature. Subsequently, derivatives were 19-22 years), and the mean body weight was 65 ± 7 kg formed with 50 µL of 10% trifluoroacetic anhydride in (range, 54-80 kg). All subjects were male nonsmokers diethylether hexane, and residues were dissolved in 20 and healthy as determined by medical history, physical µL ethyl acetate and then injected into a gas chromato- Table I. Results of genotypes and phenotypes of
CYP2C19 from 12 Chinese subjects
Genotype analysis of 77 healthy young volunteers indicates that the incidence of poor metabolizers and extensive metabolizers in Chinese Han populations was 14.3% and 85.7% (data not shown), respectively, which is consistent with previous reports.16,17 Six extensive metabolizers and 6 poor metabolizers chosen by strati-fied random selection from 66 healthy extensive metab- olizers and 11 poor metabolizers, respectively, were enrolled for the pharmacokinetic study on sertraline.
Subsequently, the results of CYP2C19 phenotypes of 12 subjects determined by use of hydroxylation indices omeprazole]) were consistent with their previous geno- The extensive metabolizers and poor metabolizers had a distinct plasma concentration-time profile for ser- traline and desmethylsertraline (Fig 1). Marked differ- EM, Extensive metabolizers; PM, poor metabolizers.
ences in the pharmacokinetic parameters of sertralineand desmethylsertraline between the extensive metabo-lizers and poor metabolizers are summarized in Table graph equipped with an electron-capture detector. Chro- II. The poor metabolizers had a 41% increase in sertra- matography was performed on a 5% phenylmethylsili- line AUC0-∞ (983.6 ± 199.3 µg · h/L versus 697.6 ± cone capillary column (30 m × 0.25 mm inner diame- 133.0 µg · h/L; P < .05) and a 51% increase in sertra- ter; Alltech, Dalian, China). The limit of detection for line terminal elimination half-life (t1⁄ ) (35.5 ± 5.6 hours both sertraline and desmethylsertraline was 3.2 nmol/L.
versus 23.5 ± 4.4 hours; P < .01) compared with exten- A good linear relationship was obtained in the range sive metabolizers. The oral clearance (CLoral) of sertra- 3.6 to 360 nmol/L for sertraline and 3.4 to 340 nmol/L line in poor metabolizers was significantly lower than for desmethylsertraline. The coefficient of variation for that in extensive metabolizers (105.3 ± 19.4 L/h versus intraday and interday reproducibility ranged from 4.3% 148.4 ± 28.6 L/h; P < .05). The AUC0-144 and Cmax of to 4.7% and 7.1% to 8.5% for sertraline and desmethylser- desmethylsertraline in poor metabolizers were signifi- cantly lower than the values in extensive metabolizers Data analysis. Pharmacokinetic analysis was per-
(627.6 ± 203.8 µg · h/L versus 972.1 ± 270.3 µg · h/L; formed by a noncompartmental approach. The area P < .05; 23.6 ± 6.5 nmol/L versus 32.4 ± 8.2 nmol/L; under the concentration versus time curve (AUC0-t) was P < .01; respectively). In addition, desmethylsertraline calculated by the trapezoidal rule from zero to the last Tmax (time to reach Cmax) in poor metabolizers was measured concentration point. The elimination rate markedly higher than that in extensive metabolizers constant (ke) of sertraline was estimated by least regres- (70.0 ± 24.5 hours versus 26.4 ± 5.4 hours; P < .01).
sion analysis. The area under the concentration versustime curve from zero hour to infinity (AUC DISCUSSION
oral clearance (CLoral) of sertraline were calculated This is the first investigation describing the role of genetically determined CYP2C19 activity in the metab-olism of sertraline in vivo. To our knowledge, the 4´- hydroxylase activity of S-mephenytoin is geneticallydetermined and mediated mainly by CYP2C19. The incidence of the phenotype of CYP2C19 that indicates where C is the drug concentration in plasma and CL is poor metabolizers is much higher in Asian populations the total body clearance of the drug from plasma.
(13%-23%) than in white populations (2%-5%).16-19 In The data were analyzed by the Student t test and 1- this study, we identified 66 (85.7%) extensive metabo- way ANOVA. The minimal statistical level of signifi- lizers and 11 (14.3%) poor metabolizers during the cance accepted was P < .05. The statistical program SAS screening of 77 Chinese subjects. The results of the (SAS Institute Inc, Cary, NC) was used for analysis.
genotype analysis are consistent with the previous CLINICAL PHARMACOLOGY & THERAPEUTICSVOLUME 70, NUMBER 1 Fig 1. Pharmacokinetic profile of sertraline (A) and desmethylsertraline (B) in 6 extensive metab-
olizers (open circles) and 6 poor metabolizers (solid circles) of CYP2C19 after single oral 100-mg
dose of sertraline.
Table II. Pharmacokinetic data (mean ± SD) of sertraline and desmethylsertraline in 6 extensive metabolizers and 6
poor metabolizers of CYP2C19
*P < .05 and **P < .01, compared with extensive metabolizers.
reports of Bertilsson et al16 and Xiao et al.17 Our pre- of enzyme kinetics between different CYP2C19 geno- vious study also indicated that two defects in the typed liver microsomes.5 In addition, the in vivo study CYP2C19 gene (m1 and m2) may account for 100% of by Hamelin et al6 reported that the disposition of ser- the Chinese poor metabolizers. The subsequent pheno- traline is not associated with the polymorphism of type analysis of 12 subjects in the study showed accord CYP2D6 and there is no effect of CYP2D6 activity on sertraline and desmethylsertraline. However, our results Sertraline is mainly metabolized to N-desmethylser- found that CYP2C19 appears to have a significant traline, an inactive metabolite, which is further hydrox- impact on the metabolism of sertraline. Both the exten- ylated at α-carbon to form a corresponding ketone, sive metabolizers and the poor metabolizers had the which can subsequently be metabolized to form an markedly different pharmacokinetic parameters of ser- amphiasteric metabolite pair.20 In vitro studies have traline and desmethylsertraline. The poor metabolizers shown that the N-demethylation of sertraline is cat- had significantly higher AUC0-∞ and t1⁄ values of ser- alyzed by multiple CYP isoforms in human liver micro- traline than the extensive metabolizers had. The CLoral somes, including CYP2B6, CYP2C9, CYP2C19, of sertraline in poor metabolizers (105.3 ± 19.4 L/h) CYP2D6, and CYP3A4.4,5 However, our recent in vitro was significantly lower than that of extensive metabo- study found that CYP2D6 and CYP3A4 appear not to lizers (148.4 ± 28.6 L/h). In addition, the AUC0-144 and be involved in the N-demethylation of sertraline and Cmax values of desmethylsertraline in poor metaboliz- that CYP2C19 may be a major enzyme contributing to ers were significantly decreased in comparison with the sertraline N-demethylation because of its high affinity respective values of extensive metabolizers. The Tmax for sertraline and the marked difference in the features value of desmethylsertraline was significantly longer in poor metabolizers than in extensive metabolizers, result there is an accumulation of sertraline. Another and Cmax in extensive metabolizers was significantly factor is that 2 poor metabolizers may have had a weak higher than that in poor metabolizers, although the ser- tolerance for sertraline. Thus poor metabolizers appear traline Cmax in extensive metabolizers was almost the to be at increased risk for accumulation of sertraline same as that for poor metabolizers. On the other hand, and the possible development of sertraline-associated extensive metabolizers had a sharper elimination phase toxicity. Therefore, when sertraline is used clinically of desmethylsertraline but this phenomenon was not for the treatment of depression and obsessive-compul- seen in poor metabolizers. These data suggest that sive disorder, it is necessary to properly decrease its CYP2C19 is probably also a major enzyme that is clinical dose for patients who are poor metabolizers of responsible for further hydroxylation of desmethylser- traline, except that it is involved in the N-demethyla- In summary, we conclude that the polymorphic CYP2C19 may be a principal enzyme involved in the The fact that gene dose has an effect on drug metabo- metabolism of sertraline, and the N-demethylation of lism has been reported previously. Broly et al21 have sertraline in Chinese subjects appears to be dependent shown that the metabolic ratio in heterozygous extensive metabolizers of CYP2D6 is significantly higher than thatin homozygous extensive metabolizers. Our previousstudies also found that gene dose can affect the metabo- References
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