Drug–drug interaction study of imatinib and voriconazole in vitro and in vivo

Background: In clinical practice, common problem polypharmacy could result in the increased risks of drug–drug interactions (DDIs). Co-administered imatinib (IMA) and voriconazole (VOR) as one treatment protocol in cancer patients with fungal infections are common.Purpose: The aim of the present study was to assess the potential DDIs associated with the concurrent use of IMA and VOR in rat liver microsomes (RLMs) and in rats.Methods and results: The concentration levels of IMA, VOR, and their metabolites N-desmethyl IMA (CGP74588) and N-oxide voriconazole (N-oxide VOR) were determined by ultra performance liquid chromatography-tandem mass spectrometry. In vitro study of RLMs, VOR inhibited the IMA metabolism with the half-maximal inhibitory concentration (IC(50)) of 105.20 μM, while IC(50) for IMA against VOR was 61.30 μM. After co-administered IMA and VOR in rats, the C(max) of IMA was increased significantly, while the AUC(0→t), AUC(0→∞), and C(max) of CGP74588 were decreased significantly. In addition, similar results were also found that the main pharmacokinetic parameters (AUC(0→t), AUC(0→∞), MRT(0→∞), T(max,) and C(max)) of VOR were increased significantly, while the AUC(0→t), AUC(0→∞), and C(max) of N-oxide VOR were decreased significantly. Incorporation of all the results indicated that both drugs had a inhibitory effect on each other’s metabolism in vitro and in vivo.Conclusion: Thus, it is of great value to monitor the concomitant use of IMA and VOR in the clinic to reduce the risks of unexpected clinical outcomes.