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Research ArticleArticle

Autoinhibition of CYP3A4 Leads to Important Role of CYP2C8 in Imatinib Metabolism: Variability in CYP2C8 Activity May Alter Plasma Concentrations and Response

Anne M. Filppula, Mikko Neuvonen, Jouko Laitila, Pertti J. Neuvonen and Janne T. Backman
Drug Metabolism and Disposition January 2013, 41 (1) 50-59; DOI: https://doi.org/10.1124/dmd.112.048017
Anne M. Filppula
Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland (A.M.F., M.N., J.L., P.J.N., J.T.B.) and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland (P.J.N., J.T.B.)
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Mikko Neuvonen
Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland (A.M.F., M.N., J.L., P.J.N., J.T.B.) and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland (P.J.N., J.T.B.)
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Jouko Laitila
Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland (A.M.F., M.N., J.L., P.J.N., J.T.B.) and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland (P.J.N., J.T.B.)
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Pertti J. Neuvonen
Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland (A.M.F., M.N., J.L., P.J.N., J.T.B.) and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland (P.J.N., J.T.B.)
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Janne T. Backman
Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland (A.M.F., M.N., J.L., P.J.N., J.T.B.) and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland (P.J.N., J.T.B.)
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Abstract

Recent data suggest that the role of CYP3A4 in imatinib metabolism is smaller than presumed. This study aimed to evaluate the quantitative importance of different cytochrome P450 (P450) enzymes in imatinib pharmacokinetics. First, the metabolism of imatinib was investigated using recombinant P450 enzymes and human liver microsomes with P450 isoform-selective inhibitors. Thereafter, an in silico model for imatinib was constructed to perform pharmacokinetic simulations to assess the roles of P450 enzymes in imatinib elimination at clinically used imatinib doses. In vitro, CYP2C8 inhibitors and CYP3A4 inhibitors inhibited the depletion of 0.1 µM imatinib by 45 and 80%, respectively, and the formation of the main metabolite of imatinib, N-desmethylimatinib, by >50%. Likewise, recombinant CYP2C8 and CYP3A4 metabolized imatinib extensively, whereas other isoforms had minor effect on imatinib concentrations. In the beginning of imatinib treatment, the fractions of its hepatic clearance mediated by CYP2C8 and CYP3A4 were predicted to approximate 40 and 60%, respectively. During long-term treatment with imatinib 400 mg once or twice daily, up to 65 or 75% of its hepatic elimination was predicted to occur via CYP2C8, and only about 35 or 25% by CYP3A4, due to dose- and time-dependent autoinactivation of CYP3A4 by imatinib. Thus, although CYP2C8 and CYP3A4 are the main enzymes in imatinib metabolism in vitro, in silico predictions indicate that imatinib inhibits its own CYP3A4-mediated metabolism, assigning a key role for CYP2C8. During multiple dosing, pharmacogenetic polymorphisms and drug interactions affecting CYP2C8 activity may cause marked interindividual variation in the exposure and response to imatinib.

Footnotes

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • dx.doi.org/10.1124/dmd.112.048017.

  • This work was supported by the Helsinki University Central Hospital Research Fund, Helsinki, Finland. Filppula was also supported by the Clinical Drug Research Graduate School (CDRGS), Helsinki, Finland and the Orion-Farmos Research Foundation, Espoo, Finland.

  • Parts of this work were previously presented at the 10th EACPT Congress (June 26–29, 2011, Budapest, Hungary) and the 19th MDO Meeting and 12th European ISSX Meeting (June 17–21, 2012, Noordwijk aan Zee, the Netherlands).

  • Received July 19, 2012.
  • Accepted October 1, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (1)
Drug Metabolism and Disposition
Vol. 41, Issue 1
1 Jan 2013
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Research ArticleArticle

Important Role for CYP2C8 in Imatinib Metabolism

Anne M. Filppula, Mikko Neuvonen, Jouko Laitila, Pertti J. Neuvonen and Janne T. Backman
Drug Metabolism and Disposition January 1, 2013, 41 (1) 50-59; DOI: https://doi.org/10.1124/dmd.112.048017

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Research ArticleArticle

Important Role for CYP2C8 in Imatinib Metabolism

Anne M. Filppula, Mikko Neuvonen, Jouko Laitila, Pertti J. Neuvonen and Janne T. Backman
Drug Metabolism and Disposition January 1, 2013, 41 (1) 50-59; DOI: https://doi.org/10.1124/dmd.112.048017
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