Publication in the prestigious Molecular Pharmacology Journal is further confirmation of the enthusiasm in academia and industry for more predictive preclinical models, and further demonstrates how these models can be used to better predict drug exposure, distribution, metabolism, and safety in humans.
The paper describes transADMET™ mice humanized for the nuclear receptors PXR & CAR and the cytochrome P450 3A4. All three are involved in the metabolism of many marketed drugs, and species differences between the human and animal proteins means that studies in conventional animals may not be predictive of man. The paper, entitled "Quantitative prediction of human pregnane X receptor and cytochrome P450 3A4 mediated drug-drug interaction in a novel multiple humanized mouse line," demonstrates that the mice can be used to rank PXR ligands according to their potency to induce CYP3A4 expression in the human liver. Crucially, the mice can also be used to quantitatively predict PXR / CYP3A4-mediated drug-drug interactions in humans.
The hPXR-hCAR-hCYP3A4 mouse is available as part of CXR's and Taconic's transADMET™ program. As for all transADMET™ models, the corresponding murine genes have been replaced with their human counterparts. transADMET™ humanized and knockout mice are now available for many of the key genes involved in drug metabolism - for instance PXR, CAR, CYP3A4, CYP2D6, CYP2C9, and MDR1.
Reference:
Quantitative prediction of human pregnane X receptor and cytochrome P450 3A4 mediated drug-drug interaction in a novel multiple humanized mouse line. Maki Hasegawa, Yury Kapelyukh, Harunobu Tahara, Jost Seibler, Anja Rode, Sylvia Krueger, Dongtao N. Lee, C. Roland Wolf, Nico Scheer. Molecular Pharmacology (2011).
Please click here to access the complete paper and supplementary data.
About CXR
CXR Biosciences Ltd. is commercializing innovative approaches to transform the drug development and chemical safety assessment process. As well as introducing new technology platforms, CXR also helps customers to take their candidate compounds through development efficiently, or to resolve problems that have been encountered, through the provision of customized solutions. The company has business relationships with many of the world's leading pharmaceutical companies, chemical companies, biotechnology companies, universities, and research institutions. CXR Biosciences Ltd. is located in Dundee, Scotland. More information can be found at www.cxrbiosciences.com.
About Kyowa Hakko Kirin
Kyowa Hakko Kirin Co., Ltd. is a Japan-based specialty pharmaceutical company that creates and sales innovative new drugs mainly in the core therapeutic areas of oncology, nephrology, and immunology. Kyowa Hakko Kirin is an R&D-centered company with a strong foundation in biotechnology, particularly state of the art antibody technologies. Kyowa Hakko Kirin strives to contribute to the health and well-being of people around the world. More information can be found at www.kyowa-kirin.co.jp/english/.
About Taconic
Taconic is a leading provider of life sciences solutions to researchers worldwide, offering innovative lab animal models and scientific services that facilitate in vivo studies and advance drug discovery. Taconic's wide range of advanced solutions include custom model design, generation and production, off-the-shelf model repositories, compound profiling, contract research, contract breeding, genetic monitoring, and health testing. Headquartered in New York's Hudson River Valley, Taconic operates seven breeding facilities and three service laboratories in the U.S. and Europe and maintains a staff of over 1,200 scientific specialists committed to technological innovation.