Pharmacokinetics of sertraline in relation to genetic polymorphism of <i>CYP2C19</i>

Jiu-hui, Wang; Liu, Zhao‐Qian; Wang, Wei; Chen, Xiaoping; Shu, Yan; He, Nan; Zhou, Hong‐Hao

doi:10.1067/mcp.2001.116513

Cited by 132 publications

(88 citation statements)

References 16 publications

(15 reference statements)

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“…Selective Serotonin Reuptake Inhibitors. CYP2C19 PMs have significantly higher concentrations of citalopram (Sindrup et al, 1993;Herrlin et al, 2003), fluoxetine , and sertraline (Wang et al, 2001). Citalopram (racemic and the active S-enantiomer) concentrations are ϳ1.7-fold higher in PMs at steady state (Sindrup et al, 1993;Herrlin et al, 2003), although no significant difference was seen after a single dose (Yu et al, 2003).…”

Section: Drugmentioning

confidence: 91%

“…Citalopram (racemic and the active S-enantiomer) concentrations are ϳ1.7-fold higher in PMs at steady state (Sindrup et al, 1993;Herrlin et al, 2003), although no significant difference was seen after a single dose (Yu et al, 2003). The AUC of sertraline was 1.4-fold higher after a single dose in Chinese volunteers (Wang et al, 2001). These small differences in AUC are of doubtful clinical significance given the lack of a clear concentration-effect relationship with this class.…”

Section: Drugmentioning

confidence: 99%

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Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

2006

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Section: Drugmentioning

confidence: 91%

Section: Drugmentioning

confidence: 99%

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

2006

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“…Furthermore, sertraline has been shown to exhibit no differences in pharmacokinetics in CYP2D6 extensive versus poor metabolizers (Hamelin et al, 1996) and minor differences in CYP2C19 extensive versus poor metabolizers (Wang et al, 2001), suggesting that neither of these enzymes predominates in the metabolic clearance of sertraline.…”

mentioning

confidence: 99%

Sertraline Is Metabolized by Multiple Cytochrome P450 Enzymes, Monoamine Oxidases, and Glucuronyl Transferases in Human: An in Vitro Study

Obach¹,

Cox²,

Tremaine³

2004

Drug Metab Dispos

178

139

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ABSTRACT:The oxidative and conjugative metabolism of sertraline was examined in vitro to identify the enzymes involved in the generation of N-desmethyl, deaminated, and N-carbamoyl-glucuronidated metabolites in humans. In human liver microsomes, sertraline was N-demethylated and deaminated by cytochrome P450 (P450) enzymes with overall K m values of 98 and 114 M, respectively, but the intrinsic clearance for N-demethylation was approximately 20-fold greater than for deamination. Using P450 isoform-selective inhibitors and recombinant heterologously expressed enzymes, it was demonstrated that several P450 enzymes catalyzed sertraline N-demethylation, with CYP2B6 contributing the greatest extent, and lesser contributions from CYP2C19, CYP2C9, CYP3A4, and CYP2D6. For deamination, data supported a role for CYP3A4 and CYP2C19. Purified human monoamine oxidases A and B also catalyzed sertraline deamination with comparable K m values (230-270 M). Monoamine oxidase B catalyzed the reaction approximately 3-fold faster than did monoamine oxidase A. Sertraline N-carbamoyl glucuronidation was measured in human liver microsomes in bicarbonate buffer and under a CO 2 atmosphere (K m ‫؍‬ 50 M) and was catalyzed at the fastest rate by recombinant human UGT2B7. The observation that multiple enzymes appear to be involved in sertraline metabolism suggests that there should be no single agent that could substantially alter the pharmacokinetics of sertraline, nor should there be any single drug-metabolizing enzyme genetic polymorphism (e.g., CYP2D6, CYP2C19, CYP2C9, UGT1A1) that could profoundly impact the pharmacokinetics of sertraline.

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“…In PMs, the parent drug had longer halflife and reduced clearance, compared with EMs. 32,33,35 A fourth study of paroxetine in healthy adults found reduced metabolic function in CYP2D6 PMs compared with EMs. 34 One multiple dose study of paroxetine reported a nonsignificant difference in median plasma concentration between homozygous wild-type EMs and heterozygous EMs (e.g., one active allele and one inactive allele).…”

Section: Recommendations From the Egapp Working Groupmentioning

confidence: 99%

“…Sixteen studies met inclusion criteria, of which five looked at metabolism of a single bolus of SSRI in healthy adults [32][33][34][35] or after a limited number of doses, 36 and 11 investigated the effects of CYP450 genotypes on the blood levels of specific SSRIs in patients at steady state doses. [37][38][39][40][41][42][43][44][45][46][47] • As expected based on the genotype, three single bolus studies of SSRI (sertraline, fluoxetine, or citalopram) metabolism in healthy adults showed that, compared with EMs, CYP2C19 PMs had significantly reduced metabolic function and significantly lower plasma concentrations of drug metabolites.…”

Section: Recommendations From the Egapp Working Groupmentioning

confidence: 99%

Recommendations from the EGAPP Working Group: testing for cytochrome P450 polymorphisms in adults with nonpsychotic depression treated with selective serotonin reuptake inhibitors

Berg

Piper

Armstrong

et al. 2007

Genetics in Medicine

135

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This statement summarizes the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group recommendations regarding CYP450 genetic testing in adult patients beginning treatment with selective serotonin reuptake inhibitors (SSRIs), and the supporting scientific evidence. EGAPP is a project developed by the National Office of Public Health Genomics at the Centers for Disease Control and Prevention to support a rigorous, evidence-based process for evaluating genetic tests and other genomic applications that are in transition from research to clinical and public health practice in the United States. A key goal of the EGAPP Working Group is to develop conclusions and recommendations regarding clinical genomic applications and to establish clear linkage to the supporting scientific evidence. The Working Group members are nonfederal experts in genetics, laboratory medicine, and clinical epidemiology convened to establish methods and processes; set priorities for review topics; participate in technical expert panels for commissioned evidence reviews; publish recommendations; and provide guidance and feedback on other project activities. Summary of RecommendationThe EGAPP Working Group found insufficient evidence to support a recommendation for or against use of CYP450 testing in adults beginning SSRI treatment for non-psychotic depression. In the absence of supporting evidence, and with consideration of other contextual issues, EGAPP discourages use of CYP450 testing for patients beginning SSRI treatment until further clinical trials are completed.

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Pharmacokinetics of sertraline in relation to genetic polymorphism of CYP2C19

Abstract: 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 sertraline.

Cited by 132 publications

References 16 publications

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

Sertraline Is Metabolized by Multiple Cytochrome P450 Enzymes, Monoamine Oxidases, and Glucuronyl Transferases in Human: An in Vitro Study

Recommendations from the EGAPP Working Group: testing for cytochrome P450 polymorphisms in adults with nonpsychotic depression treated with selective serotonin reuptake inhibitors

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