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Research ArticleArticle

A Role for Cytochrome b5 in the In Vivo Disposition of Anticancer and Cytochrome P450 Probe Drugs in Mice

Colin J. Henderson, Lesley A. McLaughlin, Robert D. Finn, Sebastien Ronseaux, Yury Kapelyukh and C. Roland Wolf
Drug Metabolism and Disposition January 2014, 42 (1) 70-77; DOI: https://doi.org/10.1124/dmd.113.055277
Colin J. Henderson
Division of Cancer Research, Medical Research Institute, University of Dundee, and Ninewells Hospital and Medical School, Dundee, United Kingdom
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Lesley A. McLaughlin
Division of Cancer Research, Medical Research Institute, University of Dundee, and Ninewells Hospital and Medical School, Dundee, United Kingdom
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Robert D. Finn
Division of Cancer Research, Medical Research Institute, University of Dundee, and Ninewells Hospital and Medical School, Dundee, United Kingdom
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Sebastien Ronseaux
Division of Cancer Research, Medical Research Institute, University of Dundee, and Ninewells Hospital and Medical School, Dundee, United Kingdom
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Yury Kapelyukh
Division of Cancer Research, Medical Research Institute, University of Dundee, and Ninewells Hospital and Medical School, Dundee, United Kingdom
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C. Roland Wolf
Division of Cancer Research, Medical Research Institute, University of Dundee, and Ninewells Hospital and Medical School, Dundee, United Kingdom
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Abstract

The role of microsomal cytochrome b5 (Cyb5) in defining the rate of drug metabolism and disposition has been intensely debated for several decades. Recently we described mouse models involving the hepatic or global deletion of Cyb5, demonstrating its central role in in vivo drug disposition. We have now used the cytochrome b5 complete null (BCN) model to determine the role of Cyb5 in the metabolism of ten pharmaceuticals metabolized by a range of cytochrome P450s, including five anticancer drugs, in vivo and in vitro. The extent to which metabolism was significantly affected by the absence of Cyb5 was substrate-dependent; AUC increased (75–245%) and clearance decreased (35–72%) for phenacetin, metoprolol, and chlorzoxazone. Tolbutamide disposition was not significantly altered by Cyb5 deletion, while for midazolam clearance was decreased by 66%. The absence of Cyb5 had no effect on gefitinib and paclitaxel disposition, while significant changes in the in vivo pharmacokinetics were measured for: cyclophosphamide [maximum plasma concentration (Cmax) and terminal half-life increased 55% and 40%, respectively], tamoxifen (AUClast and Cmax increased 370% and 233%, respectively), and anastrozole (AUC and terminal half-life increased 125% and 62%, respectively; clearance down 80%). These data provide strong evidence that both hepatic and extrahepatic Cyb5 levels are an important determinant of in vivo drug disposition catalyzed by a range of cytochrome P450s, including currently prescribed anticancer agents, and that individuality in Cyb5 expression could be a significant determinant in rates of drug disposition in man.

Footnotes

    • Received October 3, 2013.
    • Accepted October 10, 2013.
  • ↵1 Current affiliation: Department of Applied Sciences, Faculty of Health and Life Sciences, Ellison Building, Northumbria University, Newcastle, NE1 8ST, United Kingdom.

  • ↵2 Current affiliation: Novartis Institutes for BioMedical Research, Inc., 250 Massachusetts Avenue, Cambridge, Massachusetts.

  • This work was funded by a Cancer Research UK Programme Grant [C4639/A12330].

    Colin Henderson and Lesley McLaughlin are joint first authors.

  • dx.doi.org/10.1124/dmd.113.055277.

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

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (1)
Drug Metabolism and Disposition
Vol. 42, Issue 1
1 Jan 2014
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Research ArticleArticle

Cytochrome b5 in Anticancer Drug Disposition

Colin J. Henderson, Lesley A. McLaughlin, Robert D. Finn, Sebastien Ronseaux, Yury Kapelyukh and C. Roland Wolf
Drug Metabolism and Disposition January 1, 2014, 42 (1) 70-77; DOI: https://doi.org/10.1124/dmd.113.055277

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Research ArticleArticle

Cytochrome b5 in Anticancer Drug Disposition

Colin J. Henderson, Lesley A. McLaughlin, Robert D. Finn, Sebastien Ronseaux, Yury Kapelyukh and C. Roland Wolf
Drug Metabolism and Disposition January 1, 2014, 42 (1) 70-77; DOI: https://doi.org/10.1124/dmd.113.055277
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