Monitoring Non-Specific / Off-Target Effects

Xenobiotics can directly or indirectly modulate target genes' expression or functionality. Determining and quantifying these non-specific activities is an important step in most drug development programs, as in ADMET studies (i.e., SXR modulating CYPP450 3A family).

Genetically modified animal models can help in predicting and measuring non-specific effects:

  • Humanization of these target genes in animal models enables a more predictable detection of non-specific activities.
  • Reporters can be inserted in biomarker gene loci to measure induction or repression of biomarker expression.

 

Case study: Humanized CAR (constitutive androstane receptor) mice allow more predictable DMPK studies than WT mice.

Adapted from Scheer et al. J Clin Invest 2008. A novel panel of mouse models to evaluate the role of human pregnane X receptor and constitutive androstane receptor in drug response.

CAR plays a role in transcriptional regulation of drug metabolism. 

Humanized CAR Model is a More Relevant Tool for DMPK Studies

CITCO-induced activation of humanized CAR

 

CITCO is a species-specific CAR inducer activating huCAR in humanized mice.

This mimicks a human-only response in a murine environment.
 

Pharmacokinetics in humanized CAR mice

 

Midazolam and bupropion pharmacokinetics in CITCO-treated WT and huCAR mice.

Increased clearance of the drugs in humanized mice.