Differential effects of ketoconazole, itraconazole and voriconazole on the pharmacokinetics of imatinib and its main metabolite GCP74588 in rat.

The aim of the study was to develop a high performance liquid chromatography method for simultaneous determination of imatinib and CGP74588 in rat serum and study the inhibition effects of ketoconazole, itraconazole and voriconazole on pharmacokinetics of imatinib and CGP74588 in rats. In our study, we found that ketoconazole caused a significant increase (63.4%) in the AUC of imainib and a 28.8% increase in Cmax, which was greater than that of itraconazole but lower than that of voriconazole. When co-administered with voriconazole, pharmacokinetic parameters of imatinib were not significantly altered except for a 36.8% increase in the Cmax of imtinib. The Cmax of CGP74588 was decreased by 55.8% and AUC(0-∞) 49.7%, while the Vz/F and CLz/F values were increased by 1.7-fold and 1.1-fold, respectively. Itraconazole did not significantly influence the pharmacokinetic parameters of imatinib and CGP74588. The difference may be related to the different variation of inhibition sites of the three azole antifungal agents on CYP3A4 and P-gp. In clinical, when imatinib was co-administrated with ketoconazole or voriconazole, dose adjustment of imatinib should be taken into account.