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Research ArticleArticle

Reevaluation of the Microsomal Metabolism of Montelukast: Major Contribution by CYP2C8 at Clinically Relevant Concentrations

Anne M. Filppula, Jouko Laitila, Pertti J. Neuvonen and Janne T. Backman
Drug Metabolism and Disposition May 2011, 39 (5) 904-911; DOI: https://doi.org/10.1124/dmd.110.037689
Anne M. Filppula
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Jouko Laitila
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Pertti J. Neuvonen
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Janne T. Backman
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Abstract

According to published in vitro studies, cytochrome P450 3A4 catalyzes montelukast 21-hydroxylation (M5 formation), whereas CYP2C9 catalyzes 36-hydroxylation (M6), the primary step in the main metabolic pathway of montelukast. However, montelukast is a selective competitive CYP2C8 inhibitor, and our recent in vivo studies suggest that CYP2C8 is involved in its metabolism. We therefore reevaluated the contributions of different cytochrome P450 (P450) enzymes, particularly that of CYP2C8, to the hepatic microsomal metabolism of montelukast using clinically relevant substrate concentrations in vitro. The effects of P450 isoform inhibitors on montelukast metabolism were examined using pooled human liver microsomes, and montelukast oxidations by human recombinant CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5 were investigated. The results verified the central role of CYP3A4 in M5 formation. The CYP2C8 inhibitors gemfibrozil 1-O-β glucuronide and trimethoprim inhibited the depletion of 0.02 μM montelukast and formation of M6 from 0.05 μM montelukast more potently than did the CYP2C9 inhibitor sulfaphenazole. Likewise, recombinant CYP2C8 catalyzed montelukast depletion and M6 formation at a 6 times higher intrinsic clearance than did CYP2C9, whereas other P450 isoforms produced no M6. On the basis of depletion of 0.02 μM montelukast, CYP2C8 was estimated to account for 72% of the oxidative metabolism of montelukast in vivo, with a 16% contribution for CYP3A4 and 12% for CYP2C9. Moreover, CYP2C8 catalyzed the further metabolism of M6 more actively than did any other P450. In conclusion, CYP2C8 plays a major role in the main metabolic pathway of montelukast at clinically relevant montelukast concentrations in vitro.

Footnotes

  • This work was supported by the Helsinki University Central Hospital Research Fund; the Sigrid Jusélius Foundation; and the Clinical Drug Research Graduate School, Finland.

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

    doi:10.1124/dmd.110.037689.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    DDC
    diethyldithiocarbamate
    HLM
    human liver microsome(s)
    MBI
    mechanism-based inhibition
    RAF
    relative activity factor.

  • Received December 10, 2010.
  • Accepted February 2, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (5)
Drug Metabolism and Disposition
Vol. 39, Issue 5
1 May 2011
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Research ArticleArticle

Reevaluation of the Microsomal Metabolism of Montelukast: Major Contribution by CYP2C8 at Clinically Relevant Concentrations

Anne M. Filppula, Jouko Laitila, Pertti J. Neuvonen and Janne T. Backman
Drug Metabolism and Disposition May 1, 2011, 39 (5) 904-911; DOI: https://doi.org/10.1124/dmd.110.037689

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Research ArticleArticle

Reevaluation of the Microsomal Metabolism of Montelukast: Major Contribution by CYP2C8 at Clinically Relevant Concentrations

Anne M. Filppula, Jouko Laitila, Pertti J. Neuvonen and Janne T. Backman
Drug Metabolism and Disposition May 1, 2011, 39 (5) 904-911; DOI: https://doi.org/10.1124/dmd.110.037689
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