Defining Human Pathways of Drug Metabolism In Vivo through the Development of a Multiple Humanized Mouse Model.
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.
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).
Nico
N
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).
Yury
Y
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).
Anja
A
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).
Stefan
S
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).
Diana
D
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).
Lesley A
LA
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).
De
D
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).
Colin J
CJ
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) c.r.wolf@dundee.ac.uk.
C Roland
CR
Wolf
D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D023421:Models, Animal; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D004364:Pharmaceutical Preparations; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A