The impact of azole antifungal drugs on imatinib metabolism in human liver microsomes.

1. Imatinib is widely used for the treatment of hematologic malignancies. It is common that imatinib is clinically co-prescribed with azole antifungal agents since these patients are more prone to invasive antifungal infection. The present study was to investigate the effects of azole antifungal drugs, including ketoconazole, fluconazole, voriconazole, itraconazole and posaconazole on imatinib metabolism. 2. The main metabolites, 1-OH midazolam and N-desmethyl imatinib, were determined in the absence and in the presence of various levels of ketoconazole, fluconazole, voriconazole, itraconazole and posaconazole. The relevant assay was also performed to screen mechanism-based inhibitors (MBI). 3.   The inhibition ability of 1-OH midazolam formation from midazolam based on IC values was ketoconazole (0.09 µM)>itraconazole (0.31 µM)> posaconazole (0.68 µM)>voriconazole (2.10 µM) > fluconazole (8.90 µM). Similarly, the rank order of inhibitory effects on formation of N-desmethyl imatinib from imatinib was ketoconazole (4.58 µM)>itraconazole (17.45 µM)> posaconazole (31.02 µM)> voriconazole (367.9 µM) >fluconazole (1.11 mM). Posaconazole and itraconazole displayed evidence of MBI. Additionally, imatinib was also shown as a MBI of CYP3A with IC value of 5.40 µM against the midazolam. 4. The significant difference in IC values of midazolam and imatinib inhibited by azole antifungal agents was observed. The role of CYP2C8 in imatinib metabolism and imatinib autoinhibits CYP3A activity may explain this difference. Our findings suggest that the azole antifungal agents might have limited impacts on imatinib exposure by CYP3A activity.