Nuclear Receptors and Drug-Drug Interactions: How to Better Understand Potential Toxicity
Drug-drug interactions (DDI) resulting in adverse outcomes cause approximately 3% of all hospitalizations annually in the United States. This costs the health care system over a billion dollars. Fortunately, many aspects of DDI are predictable based on the increasing understanding of the mechanisms of altered absorption, distribution, metabolism and excretion (ADME).
There are improved tools for screening for potential liabilities early in the drug-discovery process. One of the main ways compounds cause pharmacokinetic interactions is through changing the activity of enzymes involved in the clearance of drugs. This is done either by inhibition or induction of specific enzymes such as cytochromes P450 (CYPs), UDP-glucuronosyltransferases (UGTs) and ATP binding cassette transporters (ABCs).
The pregnane X receptor (PXR; NR1I2) is a key player in DDI and several other nuclear receptors have been found to be xenobiotic/drug sensing receptors. These receptors help explain how one drug affects the pharmacokinetics of another by inducing drug metabolism and transport. These xenobiotic/drug sensing receptors belong to the family of ligand-activated transcription factors known as nuclear receptors.
The important xenobiotic sensing and drug metabolism inducing systems can vary greatly between animal species, causing difficulties in animal trials. Since pharmacokinetic interactions are often examined in laboratory animal models, it is important to understand these species differences when trying to choose the correct animal model.
Watch this webinar to learn about various drug screening assays that are available for identifying potential DDI in vitro. Drug screening assays improve drug safety and allow for the prioritization of drug candidates. PXR and several other important xenobiotic sensing and drug metabolism inducing systems will be described. These include Aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), Farnesoid X Receptor (FXR) and Nuclear factor-erythroid factor 2-related factor 2 (Nrf2).