PXR activators

Other than RIF and Taxol, many other commonly used clinical drugs have also been shown to activate PXR. These include peptide-mimetic HIV protease inhibitors [53], the cholesterol-lowering lovastatin and the anti-inflammatory dexamethasone [54]. A more comprehensive analysis of the effect of commonly used clinical drugs on PXR activation has recently been published by Sinz and colleagues [55]. 

Enantiospecificity of PXR-Activating Drugs and its Implication in Drug Development... 

Apart from pharmacophore-based approaches, a variety of methods were applied to decipher important ligand features of PXR activation. VolSurf descriptor-based partial least squares (PLS) regression-based models pointed toward amide responsive regions that implicated good acceptor abilities as key variables [33]. 

Schuster, D. and Langer, T. (2005) The identification of ligand features essential for PXR activation by pharmacophore modeling. Journal of Chemical Information and Modeling, 45, 431-439. 

Related to CYP activity, PXR interestingly displayed a negative correlation/association with reprodnctive toxicity. In general, PXR lowered the false positive rate of the model by lowering the model score of chemicals with nonspecific and low potency nuclear receptor activity. Robust PXR activity is an indication of potent xenos-ensing and potentially rapid metabolism. 

PXR activators in humans—clotrimazole, rifampin, and St. John s wort. 

Induction of P-gp by rifampicin has also been reported in vivo in humans. In a clinical study, duodenal biopsies were obtained and the duodenal P-gp contents in healthy volunteers were determined before and after oral administration of rifampicin at 600 mg/day for nine days (28). Treatment with rifampicin resulted in a significantly increased expression of duodenal P-gp content by 4.2-fold. In another clinical study, treatment with rifampicin at 600 mg/day for 10 days resulted in a 3.5-fold increase in intestinal P-gp in health volunteers (29). Similarly, induction of intestinal MRP2 by rifampicin (600 mg/day for 9 days) has been reported in humans. In a clinical study with 16 healthy volunteers, rifampicin induced duodenal MRP2 mRNA in 14 out of 16 individuals, while MRP2 protein was significantly induced by rifampicin in 10 out of 16 subjects (30). Interestingly, St. John s wort, a known PXR activator, also induces the expression of P-gp and MRP2 in animals and humans (31,32). 

Utilizing cell-based in vitro cotransfection assays, a large number of structurally diverse compounds have been identified as PXR activators [3], As expected, most of these compounds had been shown previously to be CYP3A inducers (Figure 4.5). Important species-specific PXR activation profiles were... 

The analyses showed that in a relatively large dataset, the retrieval of false positives was almost guaranteed if one was trying to identify a reasonable number of PXR active ligands. However, as mentioned in this presentation,... 

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