Need to dissect mechanisms of human drug induction?
The problem
A test compound was known to cause significant induction of a number of cytochrome P450 enzymes in both rodents and man. The client wished to dissect the pathways of induction in vivo, in order to interpret clinical induction data, and assess the likelihood of drug-drug interactions and other related toxicities in specific patient populations.
The challenge was to dissect the key causes of drug induction in an in vivo system.
The solution
The Pregnane X Receptor (PXR) and the Constitutive Androstane Receptor (CAR) are closely related nuclear hormone receptors that play a critical and interlinked role in Cytochrome P450 induction.
A study in the Pxr-Car Knockout Mouse model was used to elucidate the contribution of the PXR/CAR nuclear receptor system to the observed enzyme induction. PK and enzyme induction were compared in the knockout and wild type control mice after repeat dosing with test compound. If required, single knockouts could be used to elucidate the individual contribution of each nuclear receptor, and organ samples could be taken to assess any PXR- or CAR-mediated toxicity.
The Pxr-Car Knockout Mouse can be used to mechanistically dissect causes of induction and define the contribution of PXR and CAR to downstream effects on PK and toxicity.
Study design
Results - High levels of Cytochrome P450 induction (as measured by microsomal activity) were seen in wild type mice by day 7, and this resulted in rapid metabolism of the test compound and therefore minimal plasma levels at day 7.
- In contrast, significantly lower levels of enzyme induction were seen in the Pxr-Car Knockout mice. Due to this, at day 7, accumulation of test compound was observed in these mice:
Note: these results are based on actual data obtained in a confidential study carried out for a customer.
Upon further examination, this accumulation was not seen in Pxr Knockout animals, suggesting CAR plays a key role in driving enzyme induction in vivo, and it is CAR-mediated induction that will likely be the key underlying cause of any induction-related drug-drug interactions in man.
These results demonstrate that the Pxr-Car Knockout Mouse model can be used to mechanistically dissect the causes of induction, and define the contribution of PXR and CAR to downstream effects on PK and toxicity in an in vivo system.
Availability
CXR and Taconic have partnered to make the transADMET™ Pxr-Car Knockout Mouse model and Humanized PXR-CAR Mouse model commercially available.
Contract services: CXR are co-exclusive suppliers of contract research services using transADMET™ mice. We also offer consultancy and advice to our customers, and have many years of experience dissecting cause and effect of cytochrome P450 induction.
For more information on contract research services at CXR using the transADMET™ mice, contact us here or at transADMET@cxrbiosciences.com.
Off the shelf mice: Mice may be purchased directly from Taconic by both academic and for-profit customers. To purchase transADMET™ mice, please visit the relevant model webpages:
For questions regarding distribution of these models, please contact Dr. Megan MacBride.
