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Research ArticleArticle

Defining Human Pathways of Drug Metabolism In Vivo through the Development of a Multiple Humanized Mouse Model

Nico Scheer, Yury Kapelyukh, Anja Rode, Stefan Oswald, Diana Busch, Lesley A. McLaughlin, De Lin, Colin. J. Henderson and C. Roland Wolf
Drug Metabolism and Disposition November 2015, 43 (11) 1679-1690; DOI: https://doi.org/10.1124/dmd.115.065656
Nico Scheer
Taconic Biosciences GmbH, Köln, Germany (N.S., A.R.); University Medicine of Greifswald, Center of Drug Absorption and Transport (C_DAT), Department of Clinical Pharmacology, Greifswald, Germany (S.O., D.B); and Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom (Y.K., L.A.M., D.L., C.H., C.R.W)
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Yury Kapelyukh
Taconic Biosciences GmbH, Köln, Germany (N.S., A.R.); University Medicine of Greifswald, Center of Drug Absorption and Transport (C_DAT), Department of Clinical Pharmacology, Greifswald, Germany (S.O., D.B); and Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom (Y.K., L.A.M., D.L., C.H., C.R.W)
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Anja Rode
Taconic Biosciences GmbH, Köln, Germany (N.S., A.R.); University Medicine of Greifswald, Center of Drug Absorption and Transport (C_DAT), Department of Clinical Pharmacology, Greifswald, Germany (S.O., D.B); and Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom (Y.K., L.A.M., D.L., C.H., C.R.W)
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Stefan Oswald
Taconic Biosciences GmbH, Köln, Germany (N.S., A.R.); University Medicine of Greifswald, Center of Drug Absorption and Transport (C_DAT), Department of Clinical Pharmacology, Greifswald, Germany (S.O., D.B); and Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom (Y.K., L.A.M., D.L., C.H., C.R.W)
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Diana Busch
Taconic Biosciences GmbH, Köln, Germany (N.S., A.R.); University Medicine of Greifswald, Center of Drug Absorption and Transport (C_DAT), Department of Clinical Pharmacology, Greifswald, Germany (S.O., D.B); and Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom (Y.K., L.A.M., D.L., C.H., C.R.W)
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Lesley A. McLaughlin
Taconic Biosciences GmbH, Köln, Germany (N.S., A.R.); University Medicine of Greifswald, Center of Drug Absorption and Transport (C_DAT), Department of Clinical Pharmacology, Greifswald, Germany (S.O., D.B); and Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom (Y.K., L.A.M., D.L., C.H., C.R.W)
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De Lin
Taconic Biosciences GmbH, Köln, Germany (N.S., A.R.); University Medicine of Greifswald, Center of Drug Absorption and Transport (C_DAT), Department of Clinical Pharmacology, Greifswald, Germany (S.O., D.B); and Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom (Y.K., L.A.M., D.L., C.H., C.R.W)
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Colin. J. Henderson
Taconic Biosciences GmbH, Köln, Germany (N.S., A.R.); University Medicine of Greifswald, Center of Drug Absorption and Transport (C_DAT), Department of Clinical Pharmacology, Greifswald, Germany (S.O., D.B); and Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom (Y.K., L.A.M., D.L., C.H., C.R.W)
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C. Roland Wolf
Taconic Biosciences GmbH, Köln, Germany (N.S., A.R.); University Medicine of Greifswald, Center of Drug Absorption and Transport (C_DAT), Department of Clinical Pharmacology, Greifswald, Germany (S.O., D.B); and Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom (Y.K., L.A.M., D.L., C.H., C.R.W)
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Abstract

Variability in drug pharmacokinetics is a major factor in defining drug efficacy and side effects. There remains an urgent need, particularly with the growing use of polypharmacy, to obtain more informative experimental data predicting clinical outcomes. Major species differences in multiplicity, substrate specificity, and regulation of enzymes from the cytochrome P450–dependent mono-oxygenase system play a critical role in drug metabolism. To develop an in vivo model for predicting human responses to drugs, we generated a mouse, where 31 P450 genes from the Cyp2c, Cyp2d, and Cyp3a gene families were exchanged for their relevant human counterparts. The model has been improved through additional humanization for the nuclear receptors constitutive androgen receptor and pregnane X receptor that control the expression of key drug metabolizing enzymes and transporters. In this most complex humanized mouse model reported to date, the cytochromes P450 function as predicted and we illustrate how these mice can be applied to predict drug-drug interactions in humans.

Footnotes

    • Received May 22, 2015.
    • Accepted August 10, 2015.
  • ↵1 Current affiliation: Independent Consultants, Cologne, Germany.

  • N.S. and Y.K. contributed equally to this work.

  • This work was supported in part by a Cancer Research UK programme grant [C4639/A10822] awarded to C.R.W. and by the InnoProfile-Transfer grant [Grant 03IPT612X] awarded to S.O. Part of this work was supported by ITI Life Sciences, Scotland.

  • dx.doi.org/10.1124/dmd.115.065656.

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

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (11)
Drug Metabolism and Disposition
Vol. 43, Issue 11
1 Nov 2015
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Research ArticleArticle

Drug Metabolism Pathways in a Multiple Humanized Mouse Model

Nico Scheer, Yury Kapelyukh, Anja Rode, Stefan Oswald, Diana Busch, Lesley A. McLaughlin, De Lin, Colin. J. Henderson and C. Roland Wolf
Drug Metabolism and Disposition November 1, 2015, 43 (11) 1679-1690; DOI: https://doi.org/10.1124/dmd.115.065656

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Research ArticleArticle

Drug Metabolism Pathways in a Multiple Humanized Mouse Model

Nico Scheer, Yury Kapelyukh, Anja Rode, Stefan Oswald, Diana Busch, Lesley A. McLaughlin, De Lin, Colin. J. Henderson and C. Roland Wolf
Drug Metabolism and Disposition November 1, 2015, 43 (11) 1679-1690; DOI: https://doi.org/10.1124/dmd.115.065656
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