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.
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- Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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