Taconic introduces the HRN (Hepatic Reductase Null) Mouse for studies in ADME-Tox facilitating drug efficacy screening, lead selection, and lead optimization. Originally developed by Cancer Research UK and commercialized by CXR Biosciences, this conditional, targeted knockout of Por (cytochrome P450 reductase) in the liver results in inactivation of all hepatic cytochrome P450 activity. The lack of metabolism increases the circulating levels of compound thereby facilitating bioavailability studies and increasing the chances of demonstrating early in vivo efficacy, according to the company.
Although cytochrome P450 comprises a large, diverse family of proteins in both humans and animals, they can all be rendered inactive by deleting the gene for P450 reductase, the essential electron donor to all cytochrome P450 isozymes. After hepatic cytochrome P450 activity is eliminated, in vivo drug efficacy can be demonstrated more clearly and with much smaller amounts of valuable lead compounds.
In addition, this model can also provide further information on whether parent compound or metabolite(s) are responsible for observed efficacy or toxicity when compared to wild-type mice. The lack of metabolism in the HRN also enables greater exposure to compounds without repeated dosing or the use of constant infusion pumps, even with high clearance compounds. The HRN mouse allows for the true dosing of parent compounds, which may not be otherwise possible.
Filed Under: Drug Discovery