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Research ArticleArticle

CYTOCHROME P450 3A4 IS THE MAJOR ENZYME INVOLVED IN THE METABOLISM OF THE SUBSTANCE P RECEPTOR ANTAGONIST APREPITANT

Rosa I. Sanchez, Regina W. Wang, Deborah J. Newton, Ray Bakhtiar, Ping Lu, Shuet-Hing Lee Chiu, David C. Evans and Su-Er W. Huskey
Drug Metabolism and Disposition November 2004, 32 (11) 1287-1292; DOI: https://doi.org/10.1124/dmd.104.000216
Rosa I. Sanchez
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Regina W. Wang
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Deborah J. Newton
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Ray Bakhtiar
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Ping Lu
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Shuet-Hing Lee Chiu
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David C. Evans
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Su-Er W. Huskey
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Abstract

The contribution of human cytochrome P450 (P450) isoforms to the metabolism of aprepitant in humans was investigated using recombinant P450s and inhibition studies. In addition, aprepitant was evaluated as an inhibitor of human P450s. Metabolism of aprepitant by microsomes prepared from baculovirus-expressed human P450s was observed only when CYP1A2, CYP2C19, or CYP3A4 was present in the expression system. Incubation with CYP1A2 and CYP2C19 yielded only products of O-dealkylation, whereas CYP3A4 catalyzed both N- and O-dealkylation reactions. The metabolism of aprepitant by human liver microsomes was inhibited completely by ketoconazole or troleandomycin. No inhibition was observed with other P450 isoform-selective inhibitors. Aprepitant was evaluated also as a P450 inhibitor in human liver microsomes. No significant inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2D6, and CYP2E1 was observed in experiments with isoform-specific substrates (IC50 > 70 μM). Aprepitant was a moderate inhibitor of CYP3A4, with Ki values of ∼10 μM for the 1′- and 4-hydroxylation of midazolam, and the N-demethylation of diltiazem, respectively. Aprepitant was a very weak inhibitor of CYP2C9 and CYP2C19, with Ki values of 108 and 66 μM for the 7-hydroxylation of warfarin and the 4′-hydroxylation of S-mephenytoin, respectively. Collectively, these results indicated that aprepitant is both a substrate and a moderate inhibitor of CYP3A4.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.104.000216.

  • ABBREVIATIONS: CINV, chemotherapy-induced nausea and vomiting; AUC, area under the plasma concentration versus time curve; HPPH, 5-(4′-hydroxyphenyl)-5-phenylhydantoin; P450, cytochrome P450; TAO, troleandomycin; HPLC, high-performance liquid chromatography; LC-MS/MS, liquid chromatography-tandem mass spectrometry; TFA, trifluoroacetic acid; MRM, multiple reaction monitoring.

    • Received April 13, 2004.
    • Accepted August 5, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 32 (11)
Drug Metabolism and Disposition
Vol. 32, Issue 11
1 Nov 2004
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Research ArticleArticle

CYTOCHROME P450 3A4 IS THE MAJOR ENZYME INVOLVED IN THE METABOLISM OF THE SUBSTANCE P RECEPTOR ANTAGONIST APREPITANT

Rosa I. Sanchez, Regina W. Wang, Deborah J. Newton, Ray Bakhtiar, Ping Lu, Shuet-Hing Lee Chiu, David C. Evans and Su-Er W. Huskey
Drug Metabolism and Disposition November 1, 2004, 32 (11) 1287-1292; DOI: https://doi.org/10.1124/dmd.104.000216

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Research ArticleArticle

CYTOCHROME P450 3A4 IS THE MAJOR ENZYME INVOLVED IN THE METABOLISM OF THE SUBSTANCE P RECEPTOR ANTAGONIST APREPITANT

Rosa I. Sanchez, Regina W. Wang, Deborah J. Newton, Ray Bakhtiar, Ping Lu, Shuet-Hing Lee Chiu, David C. Evans and Su-Er W. Huskey
Drug Metabolism and Disposition November 1, 2004, 32 (11) 1287-1292; DOI: https://doi.org/10.1124/dmd.104.000216
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