RT Journal Article SR Electronic T1 Azole Antimycotics Differentially Affect Rifampicin-Induced Pregnane X Receptor-Mediated CYP3A4 Gene Expression JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 339 OP 348 DO 10.1124/dmd.107.018341 VO 36 IS 2 A1 Svecova, Lucie A1 Vrzal, Radim A1 Burysek, Ladislav A1 Anzenbacherova, Eva A1 Cerveny, Lukas A1 Grim, Jiri A1 Trejtnar, Frantisek A1 Kunes, Jiri A1 Pour, Milan A1 Staud, Frantisek A1 Anzenbacher, Pavel A1 Dvorak, Zdenek A1 Pavek, Petr YR 2008 UL http://dmd.aspetjournals.org/content/36/2/339.abstract AB Azole antifungal drug ketoconazole has recently been demonstrated as an inhibitor of a ligand-induced pregnane X receptor (PXR)-mediated transcriptional regulation of the CYP3A4 gene through disruption of PXR interaction with steroid receptor coactivator (SRC)-1. In contrast, other clotrimazole-derived antifungal agents are known as potent inducers of CYP3A4 through PXR. In the present study, we examined effects of azole antimycotics clotrimazole, ketoconazole, econazole, oxiconazole, miconazole, fluconazole, and itraconazole on PXR-mediated expression of CYP3A4. We investigated individual effects of the tested azoles as well as their action on rifampicin-induced PXR-mediated transactivation and expression of CYP3A4 in LS174T cell line and primary human hepatocytes, their interactions with PXR ligand-binding domain, and azole-mediated recruitment of SRC-1 to PXR. In addition, applying the pharmacodynamic approach and dose-response analysis, we aimed to describe the nature of potential interactions of tested azole antimycotics coadministered with a prototypical PXR ligand rifampicin in transactivation of CYP3A4 gene. We describe additive and antagonistic interactions of partial and full agonists of PXR nuclear receptor in the therapeutic group of azole antimycotics in rifampicin-mediated transactivation of CYP3A4. We show that oxiconazole is a highly efficacious activator of CYP3A4 transactivation, which could be antagonized by rifampicin in a competitive manner. In addition, we show that activation of the CYP3A4 promoter is a complex process, which is not exclusively determined by azole-PXR interactions, and we suggest that the ability of some azoles to affect recruitment of SRC-1 to PXR modulates their net effects in transactivation of CYP3A4 both in the absence or presence of rifampicin. The American Society for Pharmacology and Experimental Therapeutics