Results add to growing body of knowledge on innovative tool for ADMET studies
Hudson, New York - March 30, 2010 - Results of studies using Taconic's novel HRN™ (Hepatic Reductase Null) mouse were presented at the 16th North American Regional ISSX Meeting. The HRN™ mouse is part of a new Taconic portfolio of innovative models used to better predict human response to ADMET.
At the regional meeting of the ISSX (International Society for the Study of Xenobiotics) held in October in Baltimore, Maryland, researchers from Genentech presented data from studies using the HRN™ mouse, introduced commercially by Taconic in 2008 and licensed from CXR Biosciences. This conditional, targeted knockout of Por does not express cytochrome P450 reductase in the liver, and thus liver cytochrome P450s, known to play a major role in drug disposition, are inactive. As a result, it is highly useful for determining the role of hepatic P450 metabolism in ADME-Tox studies.
"Cytochrome P450 metabolism is a major confounding factor in the bioavailability of drugs, making its study vital to the advancement of drug discovery," said Taconic Senior Vice President, Client Relations, Kevin Leak. The large and diverse family of cytochrome P450 proteins in humans and animals all can be rendered inactive by deleting the gene for P450 reductase. By eliminating hepatic cytochrome P450 activity, the Taconic HRN™ mouse enables researchers to demonstrate in vivo drug efficacy more clearly, using much smaller amounts of valuable lead compounds.
Researchers from Genentech, led by Jason Boggs, Senior Research Associate, reported validation data for the HRN™ mouse during an ISSX poster presentation. The Genentech team evaluated the model by characterizing changes in pharmacokinetics of test articles in the HRN™ mouse and in wild type controls, using compounds metabolized by different human cytochrome P450s and those reflecting low, medium, and high clearance.
Intravenous dosing resulted in a greater decrease in clearance and a greater increase in half-life for docetaxel, midazolam and theophylline in the HRN™ mouse as compared to the controls. Clearance and half-life of nelfinavir was similar in both groups, indicating that it could be mediated by extra-hepatic CYP or non-CYP pathways. In comparing dosage routes for midazolam, researchers found a much larger increase in area under the curve values in HRN™ mice vs. controls with oral dosing as compared to intravenous dosing, indicating that hepatic first-pass metabolism could possibly be significant for midazolam.
The Genentech team also evaluated extra-hepatic metabolism by administering aminobenzotriazole (ABT), an inhibitor of CYP activity in the liver and other tissues. Co-administration of ABT with midazolam increased midazolam exposure in HRN™ mice, suggesting that extra-hepatic CYPs have some involvement in the compound's metabolism. Co-administration of ABT with nelfinavir resulted in little change in exposure, suggesting that non-CYP pathways are responsible for its clearance.
The Genentech research results add to the large body of data available on the HRN™ mouse, a valuable research tool for ADMET studies. Investigators can use the model to test the efficacy of compounds that show high hepatic clearance and low bioavailability in standard mouse models, or to evaluate clearance mechanisms by assessing hepatic and extra-hepatic metabolism of compounds.
Since its commercial introduction, the HRN™ model has been used by a wide variety of researchers in academic and commercial applications. Available exclusively from Taconic, the HRN™ mouse can be purchased in typical study size quantities. CXR Biosciences, which has expertise in the use of the HRN™ mouse, will also conduct contract research studies using the model.
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.
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, custom 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 1,000 scientific specialists committed to technological innovation.