Drug–drug interactions by azole antifungals: Beyond a dogma of CYP3A4 enzyme activity inhibition

Azoles antifungals are widespread used drugs for various medicinal indications. These drugs are well known for their numerous drug–drug interactions, which are believed to occur via inhibition of CYP3A4 enzymatic activity and consequently altering pharmacokinetic of co-administered drugs. In the current communication a complex view on the molecular interactions between azoles antimycotics and CYP3A4 is presented. Beside inhibition of CYP3A4 catalytic activity, azoles influence transcriptional activity of pregnane X receptor (PXR) and consequently expression of drug-metabolizing enzymes, including CYP3A4. Interactions between azoles and PXR occur by multiple mechanisms, including modulation of ligand-dependent activation of PXR (agonism, antagonism) or affecting recruitment of PXR co-activators SRC-1 (steroid receptor co-activator 1) and HNF4α (hepatocyte nuclear factor 4α). Miconazole and ketoconazole are antagonists of glucocorticoid receptor (GR), therefore these drugs inhibit GR-mediated expression of PXR and drug metabolizing cytochromes P450. In addition, PXR and GR are key regulators of intermediary metabolism (e.g. carbohydrate, lipids or bile acids homeostasis) and many other cellular functions (e.g. immune response), hence, the interactions between azoles and PXR/GR are of broader physiological importance. In conclusion, while inhibition of CYP3A4 enzymatic activity by azoles is considered as primary cause of azoles drug–drug interactions, the effects of azoles on PXR and GR should be taken in account. Apart from CYP3A4, azoles influence the expression and activity of others drug-metabolizing cytochromes P450.