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Review ArticleReview Article

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

Janne T. Backman, Anne M. Filppula, Mikko Niemi and Pertti J. Neuvonen
Markku Koulu, ASSOCIATE EDITOR
Pharmacological Reviews January 2016, 68 (1) 168-241; DOI: https://doi.org/10.1124/pr.115.011411
Janne T. Backman
Department of Clinical Pharmacology, University of Helsinki (J.T.B., A.M.F., M.N., P.J.N.), and Helsinki University Hospital, Helsinki, Finland (J.T.B., M.N., P.J.N.)
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Anne M. Filppula
Department of Clinical Pharmacology, University of Helsinki (J.T.B., A.M.F., M.N., P.J.N.), and Helsinki University Hospital, Helsinki, Finland (J.T.B., M.N., P.J.N.)
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Mikko Niemi
Department of Clinical Pharmacology, University of Helsinki (J.T.B., A.M.F., M.N., P.J.N.), and Helsinki University Hospital, Helsinki, Finland (J.T.B., M.N., P.J.N.)
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Pertti J. Neuvonen
Department of Clinical Pharmacology, University of Helsinki (J.T.B., A.M.F., M.N., P.J.N.), and Helsinki University Hospital, Helsinki, Finland (J.T.B., M.N., P.J.N.)
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Markku Koulu
Department of Clinical Pharmacology, University of Helsinki (J.T.B., A.M.F., M.N., P.J.N.), and Helsinki University Hospital, Helsinki, Finland (J.T.B., M.N., P.J.N.)
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Abstract

During the last 10-15 years, cytochrome P450 (CYP) 2C8 has emerged as an important drug-metabolizing enzyme. CYP2C8 is highly expressed in human liver and is known to metabolize more than 100 drugs. CYP2C8 substrate drugs include amodiaquine, cerivastatin, dasabuvir, enzalutamide, imatinib, loperamide, montelukast, paclitaxel, pioglitazone, repaglinide, and rosiglitazone, and the number is increasing. Similarly, many drugs have been identified as CYP2C8 inhibitors or inducers. In vivo, already a small dose of gemfibrozil, i.e., 10% of its therapeutic dose, is a strong, irreversible inhibitor of CYP2C8. Interestingly, recent findings indicate that the acyl-β-glucuronides of gemfibrozil and clopidogrel cause metabolism-dependent inactivation of CYP2C8, leading to a strong potential for drug interactions. Also several other glucuronide metabolites interact with CYP2C8 as substrates or inhibitors, suggesting that an interplay between CYP2C8 and glucuronides is common. Lack of fully selective and safe probe substrates, inhibitors, and inducers challenges execution and interpretation of drug-drug interaction studies in humans. Apart from drug-drug interactions, some CYP2C8 genetic variants are associated with altered CYP2C8 activity and exhibit significant interethnic frequency differences. Herein, we review the current knowledge on substrates, inhibitors, inducers, and pharmacogenetics of CYP2C8, as well as its role in clinically relevant drug interactions. In addition, implications for selection of CYP2C8 marker and perpetrator drugs to investigate CYP2C8-mediated drug metabolism and interactions in preclinical and clinical studies are discussed.

Footnotes

  • This work was supported by grants from the Academy of Finland [Grant decision 278123, 2014], the Helsinki University Central Hospital Research Fund, and the Sigrid Juselius Foundation (Helsinki, Finland).

  • dx.doi.org/10.1124/pr.115.011411.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Pharmacological Reviews: 68 (1)
Pharmacological Reviews
Vol. 68, Issue 1
1 Jan 2016
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Review ArticleReview Article

Role of CYP2C8 in Drug Metabolism and Interactions

Janne T. Backman, Anne M. Filppula, Mikko Niemi and Pertti J. Neuvonen
Pharmacological Reviews January 1, 2016, 68 (1) 168-241; DOI: https://doi.org/10.1124/pr.115.011411

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Review ArticleReview Article

Role of CYP2C8 in Drug Metabolism and Interactions

Janne T. Backman, Anne M. Filppula, Mikko Niemi and Pertti J. Neuvonen
Pharmacological Reviews January 1, 2016, 68 (1) 168-241; DOI: https://doi.org/10.1124/pr.115.011411
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  • Article
    • Abstract
    • I. Introduction
    • II. Basic Characteristics of Cytochrome P450 2C8
    • III. Substrates of Cytochrome P450 2C8
    • IV. Pharmacogenetics
    • V. In Vitro Inhibition and Induction of Cytochrome P450 2C8
    • VI. Clinical Drug Interactions Mediated via Cytochrome P450 2C8
    • VII. Points to Consider When Investigating Cytochrome P450 2C8-Mediated Drug Metabolism and Interactions
    • VIII. Conclusions and Future Prospects
    • Acknowledgments
    • Authorship Contributions
    • Footnotes
    • Abbreviations
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