Metabolism of pimozide by CYF3A and CYP2D6 in human liver microsomes

D. A. Flockhart, E. Richard, N. Soukova, T. Kerbuscb

Research output: Contribution to journalArticle

Abstract

The potent neuroleptic pimozide is associated with prolongation of the electrocardiographic QT interval and sudden cardiac death. Case reports of increased pimozide cardiotoxicity with paroxetine, fluoxetine and clarithromycin suggest that the cytochrome P450 system may catalyze pimozide metabolism, but the specific isoforms that may be involved have not been defined. We characterized the metabolism of pimozide in vitro using whole human liver microsomes and recombinant cytochrome P450 enzymes. Recombinant CYP3A catalyzed the N-dealkylation of pimozide and ketoconazole potently inhibited this reaction in whole human liver microsomes (Ki = 1.2 ± 0.2 μM). Recombinant CYP2D6 did not catalyze the same reaction, but did catalyze discreet metabolism that was prevented by 10nM quinidine in whole human microsomes. Inhibitors of CYP1A2, CYP2C9, CYP2C19 and CYP2E1 did not affect pimozide metabolism. These data suggest that decreased activity of CYP3A or CYP2D6 may increase the cardiotoxic risk of pimozide.

Original languageEnglish (US)
Pages (from-to)232
Number of pages1
JournalClinical Pharmacology and Therapeutics
Volume61
Issue number2
StatePublished - 1997
Externally publishedYes

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Pimozide
Cytochrome P-450 CYP2D6
Liver Microsomes
Cytochrome P-450 Enzyme System
Cytochrome P-450 CYP3A
Dealkylation
Paroxetine
Quinidine
Ketoconazole
Clarithromycin
Fluoxetine
Sudden Cardiac Death
Microsomes
Antipsychotic Agents
Protein Isoforms

ASJC Scopus subject areas

  • Pharmacology

Cite this

Flockhart, D. A., Richard, E., Soukova, N., & Kerbuscb, T. (1997). Metabolism of pimozide by CYF3A and CYP2D6 in human liver microsomes. Clinical Pharmacology and Therapeutics, 61(2), 232.

Metabolism of pimozide by CYF3A and CYP2D6 in human liver microsomes. / Flockhart, D. A.; Richard, E.; Soukova, N.; Kerbuscb, T.

In: Clinical Pharmacology and Therapeutics, Vol. 61, No. 2, 1997, p. 232.

Research output: Contribution to journalArticle

Flockhart, DA, Richard, E, Soukova, N & Kerbuscb, T 1997, 'Metabolism of pimozide by CYF3A and CYP2D6 in human liver microsomes', Clinical Pharmacology and Therapeutics, vol. 61, no. 2, pp. 232.
Flockhart, D. A. ; Richard, E. ; Soukova, N. ; Kerbuscb, T. / Metabolism of pimozide by CYF3A and CYP2D6 in human liver microsomes. In: Clinical Pharmacology and Therapeutics. 1997 ; Vol. 61, No. 2. pp. 232.
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