Effect of selective serotonin reuptake inhibitors (SSRIS) and clonidine on the secondary metabolism of tamoxifen (TAM) by genetically polymorphic CYP2D6

D. A. Flockhart, N. V. Soukhova, Zeruesenay Desta

Research output: Contribution to journalArticle

Abstract

TAM is often co-prescribed with SSRI antidepressants or clonidine to reduce TAM-induced hot flashes. We tested the ability of selected SSRIs and clonidine to inhibit the formation of 4-hydroxy N-desmethyltamoxifen (4-OHNDTAM) from N-desmethyltamoxifen (NDTAM) by recombinant human CYP2D6. This study is based on our observation that in plasma samples of patients who were on tamoxifen, paroxetine decreased plasma concentrations of a metabolite that has not been clinically characterized before. We subsequently confirmed the identity of this metabolite as 4-OHNDTAM and in vitro it is primarily formed from NDTAM by CYP2D6. Incubation of 10 μM clonidine, sertraline, fluoxetine, paroxetine and 1μM quinidine (positive control) inhibit the formation of 4-OHNDTAM from NDTAM by 68, 82, 83, 100 and 92% respectively. The Ki μM) values estimated from Dixon plots for fluoxetine and paroxetine were 1.07 and 1.8μM respectively. Further inhibition was observed during preincubation of fluoxetine and paroxetine with HLMs and NADPH before reaction was started with substrate probes. Treatment of TAM-induced hot flashes by SSRIs and clonidine may in part be due to inhibition of CYP2D6-mediated 4-OHNDTAM formation in vivo and it is possible that poor metabolizers of CYP2D6 are at less risk for hot flashes than extensive metabolizers.

Original languageEnglish (US)
JournalClinical Pharmacology and Therapeutics
Volume69
Issue number2
StatePublished - 2001
Externally publishedYes

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Secondary Metabolism
Cytochrome P-450 CYP2D6
Paroxetine
Serotonin Uptake Inhibitors
Clonidine
Tamoxifen
Hot Flashes
Fluoxetine
Sertraline
Quinidine
NADP
Antidepressive Agents
N-desmethyltamoxifen

ASJC Scopus subject areas

  • Pharmacology

Cite this

@article{5978a0b248564a0d8ee78e8d02a9e4a5,
title = "Effect of selective serotonin reuptake inhibitors (SSRIS) and clonidine on the secondary metabolism of tamoxifen (TAM) by genetically polymorphic CYP2D6",
abstract = "TAM is often co-prescribed with SSRI antidepressants or clonidine to reduce TAM-induced hot flashes. We tested the ability of selected SSRIs and clonidine to inhibit the formation of 4-hydroxy N-desmethyltamoxifen (4-OHNDTAM) from N-desmethyltamoxifen (NDTAM) by recombinant human CYP2D6. This study is based on our observation that in plasma samples of patients who were on tamoxifen, paroxetine decreased plasma concentrations of a metabolite that has not been clinically characterized before. We subsequently confirmed the identity of this metabolite as 4-OHNDTAM and in vitro it is primarily formed from NDTAM by CYP2D6. Incubation of 10 μM clonidine, sertraline, fluoxetine, paroxetine and 1μM quinidine (positive control) inhibit the formation of 4-OHNDTAM from NDTAM by 68, 82, 83, 100 and 92{\%} respectively. The Ki μM) values estimated from Dixon plots for fluoxetine and paroxetine were 1.07 and 1.8μM respectively. Further inhibition was observed during preincubation of fluoxetine and paroxetine with HLMs and NADPH before reaction was started with substrate probes. Treatment of TAM-induced hot flashes by SSRIs and clonidine may in part be due to inhibition of CYP2D6-mediated 4-OHNDTAM formation in vivo and it is possible that poor metabolizers of CYP2D6 are at less risk for hot flashes than extensive metabolizers.",
author = "Flockhart, {D. A.} and Soukhova, {N. V.} and Zeruesenay Desta",
year = "2001",
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T1 - Effect of selective serotonin reuptake inhibitors (SSRIS) and clonidine on the secondary metabolism of tamoxifen (TAM) by genetically polymorphic CYP2D6

AU - Flockhart, D. A.

AU - Soukhova, N. V.

AU - Desta, Zeruesenay

PY - 2001

Y1 - 2001

N2 - TAM is often co-prescribed with SSRI antidepressants or clonidine to reduce TAM-induced hot flashes. We tested the ability of selected SSRIs and clonidine to inhibit the formation of 4-hydroxy N-desmethyltamoxifen (4-OHNDTAM) from N-desmethyltamoxifen (NDTAM) by recombinant human CYP2D6. This study is based on our observation that in plasma samples of patients who were on tamoxifen, paroxetine decreased plasma concentrations of a metabolite that has not been clinically characterized before. We subsequently confirmed the identity of this metabolite as 4-OHNDTAM and in vitro it is primarily formed from NDTAM by CYP2D6. Incubation of 10 μM clonidine, sertraline, fluoxetine, paroxetine and 1μM quinidine (positive control) inhibit the formation of 4-OHNDTAM from NDTAM by 68, 82, 83, 100 and 92% respectively. The Ki μM) values estimated from Dixon plots for fluoxetine and paroxetine were 1.07 and 1.8μM respectively. Further inhibition was observed during preincubation of fluoxetine and paroxetine with HLMs and NADPH before reaction was started with substrate probes. Treatment of TAM-induced hot flashes by SSRIs and clonidine may in part be due to inhibition of CYP2D6-mediated 4-OHNDTAM formation in vivo and it is possible that poor metabolizers of CYP2D6 are at less risk for hot flashes than extensive metabolizers.

AB - TAM is often co-prescribed with SSRI antidepressants or clonidine to reduce TAM-induced hot flashes. We tested the ability of selected SSRIs and clonidine to inhibit the formation of 4-hydroxy N-desmethyltamoxifen (4-OHNDTAM) from N-desmethyltamoxifen (NDTAM) by recombinant human CYP2D6. This study is based on our observation that in plasma samples of patients who were on tamoxifen, paroxetine decreased plasma concentrations of a metabolite that has not been clinically characterized before. We subsequently confirmed the identity of this metabolite as 4-OHNDTAM and in vitro it is primarily formed from NDTAM by CYP2D6. Incubation of 10 μM clonidine, sertraline, fluoxetine, paroxetine and 1μM quinidine (positive control) inhibit the formation of 4-OHNDTAM from NDTAM by 68, 82, 83, 100 and 92% respectively. The Ki μM) values estimated from Dixon plots for fluoxetine and paroxetine were 1.07 and 1.8μM respectively. Further inhibition was observed during preincubation of fluoxetine and paroxetine with HLMs and NADPH before reaction was started with substrate probes. Treatment of TAM-induced hot flashes by SSRIs and clonidine may in part be due to inhibition of CYP2D6-mediated 4-OHNDTAM formation in vivo and it is possible that poor metabolizers of CYP2D6 are at less risk for hot flashes than extensive metabolizers.

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