In vitro inhibition of pimozide N-dealkylation by selective serotonin reuptake inhibitors (SSRIS) antidepressants and azithromycin

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

Research output: Contribution to journalArticle

Abstract

We tested the inhibition of pimozide N-dealkylation by 4 SSRI and azithromycin in human liver microsomes (HLMs). All data are averages from 3 HLMs. Pimozide (10 μM) metabolism was inhibited by an average of 6%, 7%, 19% and 23% with 10μM fluoxetine, paroxetine, sertraline and fluvoxamine respectively, while this inhibition did not exceed 54% at 100μM SSRIs. Azithromycin had a negligible effect on pimozide N-dealkylation (19% at 100μM). At 0.1 and 0.5μM ketoconazole (positive control), pimozide N-dealkylation was inhibited by 32% and 62% respectively (Ki=0.07μM). The estimated Ki values (μ.M) of sertraline, fluvoxamine, azithromycin, fluoxetine and paroxetine were 89, 89, 103, 117 and 129 respectively. Coadministration of SSRIs and azithromycin are unlikely to markedly diminish the elimination of pimozide in patients.

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

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Dealkylation
Pimozide
Azithromycin
Serotonin Uptake Inhibitors
Antidepressive Agents
Fluvoxamine
Sertraline
Paroxetine
Fluoxetine
Liver Microsomes
Ketoconazole
In Vitro Techniques

ASJC Scopus subject areas

  • Pharmacology

Cite this

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title = "In vitro inhibition of pimozide N-dealkylation by selective serotonin reuptake inhibitors (SSRIS) antidepressants and azithromycin",
abstract = "We tested the inhibition of pimozide N-dealkylation by 4 SSRI and azithromycin in human liver microsomes (HLMs). All data are averages from 3 HLMs. Pimozide (10 μM) metabolism was inhibited by an average of 6{\%}, 7{\%}, 19{\%} and 23{\%} with 10μM fluoxetine, paroxetine, sertraline and fluvoxamine respectively, while this inhibition did not exceed 54{\%} at 100μM SSRIs. Azithromycin had a negligible effect on pimozide N-dealkylation (19{\%} at 100μM). At 0.1 and 0.5μM ketoconazole (positive control), pimozide N-dealkylation was inhibited by 32{\%} and 62{\%} respectively (Ki=0.07μM). The estimated Ki values (μ.M) of sertraline, fluvoxamine, azithromycin, fluoxetine and paroxetine were 89, 89, 103, 117 and 129 respectively. Coadministration of SSRIs and azithromycin are unlikely to markedly diminish the elimination of pimozide in patients.",
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AU - Soukhova, N. V.

AU - Flockhart, D. A.

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N2 - We tested the inhibition of pimozide N-dealkylation by 4 SSRI and azithromycin in human liver microsomes (HLMs). All data are averages from 3 HLMs. Pimozide (10 μM) metabolism was inhibited by an average of 6%, 7%, 19% and 23% with 10μM fluoxetine, paroxetine, sertraline and fluvoxamine respectively, while this inhibition did not exceed 54% at 100μM SSRIs. Azithromycin had a negligible effect on pimozide N-dealkylation (19% at 100μM). At 0.1 and 0.5μM ketoconazole (positive control), pimozide N-dealkylation was inhibited by 32% and 62% respectively (Ki=0.07μM). The estimated Ki values (μ.M) of sertraline, fluvoxamine, azithromycin, fluoxetine and paroxetine were 89, 89, 103, 117 and 129 respectively. Coadministration of SSRIs and azithromycin are unlikely to markedly diminish the elimination of pimozide in patients.

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