PMID: 11910261Mar 23, 2002Paper

In vitro inhibition of pimozide N-dealkylation by selective serotonin reuptake inhibitors and azithromycin

Journal of Clinical Psychopharmacology
Zeruesenay DestaD A Flockhart

Abstract

Pimozide is often coprescribed with serotonin reuptake inhibitor (SSRI) antidepressants to treat depression in patients with Tourette's syndrome. In human liver microsomes (HLMs), the inhibition of the primary route of pimozide metabolism, N-dealkylation to 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one (DHPBI), by four SSRIs (fluoxetine, sertraline, paroxetine, and fluvoxamine) and azithromycin was tested. Inhibition constants (K(i) values) were estimated from Dixon plots (three HLMs for each inhibitor) using the appropriate enzyme inhibition model by nonlinear regression. At 10 microM paroxetine, sertraline, fluoxetine, or fluvoxamine, the formation of DHPBI from pimozide (10 microM) in HLMs was inhibited by an average (three HLMs) of 7%, 7.7%, 8%, and 16%, respectively, whereas this inhibition did not exceed 55% at the maximum concentrations (100 microM) of the SSRIs tested. Azithromycin had negligible effect on pimozide (10 microM) N-dealkylation (19% at 100 microM azithromycin). These inhibition data were compared with ketoconazole, which was included as a positive control of CYP3A inhibition. At 0.1 microM and 0.5 microM ketoconazole, the formation of DHPBI from 10 microM pimozide was inhibited by 32% and 62%, respec...Continue Reading

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Citations

Aug 10, 2013·Biopharmaceutics & Drug Disposition·Yasuhiro Masubuchi, Yuki Kawaguchi
Jul 5, 2019·Expert Opinion on Drug Metabolism & Toxicology·Donatella MarazzitiLiliana Dell'Osso
Dec 19, 2019·Pharmacogenetics and Genomics·Rachel HuddartTeri E Klein
Aug 28, 2020·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Brian D ChapronJ Steven Leeder

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