Drug development with nuclear receptor knockout and humanized rat models

Sponsored by: Horizon Discovery

Speakers

Kevin Forbes, PhD

Manager, In Vivo Research and Development , Horizon Discovery
BIOGRAPHY
Andrew Brown, MS

Product Manager, In Vivo, Horizon Discovery
BIOGRAPHY

Event Date & Time

DATE: May 22, 2018

TIME: 08:00AM PDT

Abstract

The nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are closely related transcription factors that regulate the expression of Phase I (Cytochrome P450s), Phase II drug metabolizing enzymes and drug transporter genes in response to stimulation from xenobiotics including prescription drugs . PXR and CAR knockout and humanized mouse models have proven useful. However, the rat being bigger in size, is a preferred model system for studying drug metabolism and pharmacokinetics. Here, we report the creation and preliminary characterization of PXR and CAR knockout rats and PXR/CAR double knockout rats. Whereas the expression of phase I and II enzymes and transporter genes were not upregulated by nuclear receptor-specific agonists in the knockout rats, confirming the disruption of respective nuclear receptor(s). Our data demonstrate that PXR appears to suppress the basal expression levels of specific drug metabolism genes, while CAR maintains and suppresses other drug metabolism genes. Overall, our findings are in good agreement with data obtained from human primary hepatocytes, nuclear receptor knock-out cell lines and mouse knock-out models. We believe these models are a useful complement to their mouse counterparts for drug development and as importantly, for functional studies on metabolic pathways involving nuclear receptors.

Learning Objectives:

Understand the benefit of rat models versus mouse models in functional studies on metabolic pathways
Demonstrate the utility of the PXR and CAR KO rat models
How rat hepatocytes can add value to drug development studies