Identification of Clinically Used Drugs That Activate Pregnane X Receptors

Abstract

ABSTRACT:The pregnane X receptor (PXR) binds xenobiotics and regulates the expression of several drug-metabolizing enzymes and transporters. Human PXR (hPXR) activation and CYP3A4 induction can be involved in drug-drug interactions, resulting in reduced efficacy or increased toxicity. However, there are known species-specific differences with regard to PXR activation that should be taken into account when animal PXR data are extrapolated to humans. We profiled 2816 clinically used drugs from the National Institutes of Health Chemical Genomics Center Pharmaceutical Collection for their ability to activate hPXR and rat PXR (rPXR) at the cellular level, induce human CYP3A4 at the cellular level, and bind human PXR at the protein level. From 6 to 11% of drugs were identified as active across the four assays, which included assay-specific and pan-active compounds. The lowest concordance was observed between the hPXR and rPXR assays, and many compounds active in both assays nonetheless demonstrated significant potency differences between species. Analysis based on clustering potency values demonstrated the greatest activity correlation between the hPXR activation and CYP3A4 induction assays. Structure-activity relationship analysis identified chemical scaffolds that were panactive (e.g., dihydropyridine calcium channel blockers) and others that were uniquely active in individual assays (e.g., steroids and fatty acids). These results provide important information on PXR activation by clinically used drugs, highlight the species specificity of PXR activation by xenobiotics, and provide a means of prioritizing compounds for follow-up studies and optimization efforts.

Pregnane X Receptor Activation Attenuates Inflammation-Associated Intestinal Epithelial Barrier Dysfunction by Inhibiting Cytokine-Induced Myosin Light-Chain Kinase Expression and c-Jun N-Terminal Kinase 1/2 Activation

“…Highly expressed in the liver and intestinal epithelium, the PXR has been previously characterized as a master regulator of xenobiotic metabolism and clearance (Watkins et al, 2002;Staudinger et al, 2006;Shukla et al, 2011;Dou et al, 2013;Pondugula and Mani, 2013). Acting as a sensor of exogenous chemicals, the PXR's activation leads to the expression of a variety of target genes related to detoxification and efflux pathways.…”

A Perspective on the Prediction of Drug Pharmacokinetics and Disposition in Drug Research and Development

“…The SAR for induction is not well established, which complicates the ability of drug discovery teams to limit induction liabilities when using a lower throughput and costly system such as cultured human hepatocytes. The use of ligand binding and reporter gene assays may allow higher throughput screening when attempting to do SAR and move away from an induction liability, but there are significant disconnects in the translation between these assays and induction in human hepatocytes (Shukla et al, 2011). It is therefore important to follow up positive results in ligand binding or reporter gene assays with studies in hepatocytes.…”

Utility of DPX2 Cells for Predicting CYP3A Induction-Mediated Drug-Drug Interactions and Associated Structure-Activity Relationships

“…Despite that human hepatocytes are generally considered the "preferred system" for predicting clinical inducers, their use in high-throughput screening and structure-activity relationship (SAR) studies during early discovery is limited because of the associated costs and the variability between hepatocyte lots. DPX2 cells can readily surmount such issues (Shukla et al, 2011).…”