No clinically relevant CYP3A induction after St. John’s wort with low hyperforin content in healthy volunteers

Objective Induction of CYP3A by St. John’s wort (SJW) products with high hyperforin content is well described. Since CYP3A induction is mediated by hyperforin in a concentration-dependent manner, and SJW preparations differ significantly in hyperforin content, the aim of the study was to evaluate the effect of an SJW powder with low hyperforin content on CYP3A function. Methods Twenty healthy male volunteers received an SJW powder with low hyperforin content for 2 weeks. Midazolam plasma concentration time profiles were characterized after a single oral dose of 7.5 mg midazolam on the day before and on the 14th day of SJW medication. Results Midazolam AUC0–∞ slightly decreased from 124.0 ± 62.5 ng/ml·h at baseline to 105.6 ± 53.2 ng/ml·h after SJW (P < 0.05), representing a mean 11.3% decrease (95% CI: −22.8 to 0.21). No significant change in midazolam Cmax, t1/2 and tmax was observed. For all pharmacokinetic parameters, the 90% CI for the geometric mean ratio of treatment over baseline were within the no-effect boundaries of 0.70–1.43. Conclusion Administration of an SJW product with low hyperforin content resulted in a mild induction of CYP3A not considered clinically relevant

Elucidating the ‘Jekyll and Hyde’ Nature of PXR: The Case for Discovering Antagonists or Allosteric Antagonists

The pregnane X receptor belongs to the nuclear hormone receptor superfamily and is involved in the transcriptional control of numerous genes. It was originally thought that it was a xenobiotic sensor controlling detoxification pathways. Recent studies have shown an increasingly important role in inflammation and cancer, supporting its function in abrogating tissue damage. PXR orthologs and PXR-like pathways have been identified in several non-mammalian species which corroborate a conserved role for PXR in cellular detoxification. In summary, PXR has a multiplicity of roles in vivo and is being revealed as behaving like a “Jekyll and Hyde” nuclear hormone receptor. The importance of this review is to elucidate the need for discovery of antagonists of PXR to further probe its biology and therapeutic applications. Although several PXR agonists are already reported, virtually nothing is known about PXR antagonists. Here, we propose the development of PXR antagonists through chemical, genetic and molecular modeling approaches. Based on this review it will be clear that antagonists of PXR and PXR-like pathways will have widespread utility in PXR biology and therapeutics