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Research ArticleArticle

Escitalopram (S-Citalopram) and Its Metabolites in Vitro: Cytochromes Mediating Biotransformation, Inhibitory Effects, and Comparison to R-Citalopram

Lisa L. von Moltke, David J. Greenblatt, Gina M. Giancarlo, Brian W. Granda, Jerold S. Harmatz and Richard I. Shader
Drug Metabolism and Disposition August 2001, 29 (8) 1102-1109;
Lisa L. von Moltke
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David J. Greenblatt
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Gina M. Giancarlo
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Brian W. Granda
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Jerold S. Harmatz
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Richard I. Shader
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Abstract

Transformation of escitalopram (S-CT), the pharmacologically active S-enantiometer of citalopram, to S-desmethyl-CT (S-DCT), and ofS-DCT to S-didesmethyl-CT (S-DDCT), was studied in human liver microsomes and in expressed cytochromes (CYPs). Biotransformation of theR-enantiomer (R-CT) was studied in parallel. S-CT was transformed to S-DCT by CYP2C19 (Km = 69 μM), CYP2D6 (Km = 29 μM), and CYP3A4 (Km = 588 μM). After normalization for hepatic abundance, relative contributions to net intrinsic clearance were 37% for CYP2C19, 28% for CYP2D6, and 35% for CYP3A4. At 10 μM S-CT in liver microsomes,S-DCT formation was reduced to 60% of control by 1 μM ketoconazole, and to 80 to 85% of control by 5 μM quinidine or 25 μM omeprazole. S-DDCT was formed fromS-DCT only by CYP2D6; incomplete inhibition by quinidine in liver microsomes indicated participation of a non-CYP pathway. Based on established index reactions, S-CT andS-DCT were negligible inhibitors (IC50> 100 μM) of CYP1A2, -2C9, -2C19, -2E1, and -3A, and weakly inhibited CYP2D6 (IC50 = 70–80 μM).R-CT and its metabolites, studied using the same procedures, had properties very similar to those of the correspondingS-enantiomers. Thus S-CT, biotransformed by three CYP isoforms in parallel, is unlikely to be affected by drug interactions or genetic polymorphisms. S-CT andS-DCT are also unlikely to cause clinically important drug interactions via CYP inhibition.

Footnotes

  •  This work was supported by Grants MH-01237, MH-58435, MH-34223, DA-13209, DK/AI-58496, and DA-05258 from the Department of Health and Human Services, and by a grant from Forest Laboratories, New York, NY.

  • Abbreviations used are::
    CT
    citalopram
    DCT
    desmethylcitalopram
    DDCT
    didesmethylcitalopram
    CYP
    cytochrome P450
    SSRI
    selective serotonin reuptake inhibitor
    • Received January 2, 2001.
    • Accepted April 16, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (8)
Drug Metabolism and Disposition
Vol. 29, Issue 8
1 Aug 2001
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Research ArticleArticle

Escitalopram (S-Citalopram) and Its Metabolites in Vitro: Cytochromes Mediating Biotransformation, Inhibitory Effects, and Comparison to R-Citalopram

Lisa L. von Moltke, David J. Greenblatt, Gina M. Giancarlo, Brian W. Granda, Jerold S. Harmatz and Richard I. Shader
Drug Metabolism and Disposition August 1, 2001, 29 (8) 1102-1109;

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Research ArticleArticle

Escitalopram (S-Citalopram) and Its Metabolites in Vitro: Cytochromes Mediating Biotransformation, Inhibitory Effects, and Comparison to R-Citalopram

Lisa L. von Moltke, David J. Greenblatt, Gina M. Giancarlo, Brian W. Granda, Jerold S. Harmatz and Richard I. Shader
Drug Metabolism and Disposition August 1, 2001, 29 (8) 1102-1109;
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