Differential Impacts of Azole Antifungal Drugs on the Pharmacokinetic Profiles of Dasatinib in Rats by LC-MS-MS.

Abstract

Dasatinib, as an oral multi-targeted inhibitor of BCR-ABL and SRC family kinases, has been widely used for the treatment of Philadelphia Chromosome Positive Leukemias in imatinib-acquired resistance and intolerance. The study aimed to develop and validate a simple and robust assay with a small volume of plasma based on liquid chromatography coupled with tandem mass spectrometry to determine the concentration of dasatinib and to investigate the impact of the cytochrome 3A4 inhibitors, including ketoconazole, voriconazole, itraconazole and posaconazole, on the pharmacokinetics of dasatinib in rats. Thirty rats were divided randomly into five groups, control group (0.5% carboxymethylcellulose sodium), ketoconazole (30 mg/kg) group, voriconazole group (30 mg/kg), itraconazole group (30 mg/kg) and posaconazole group (30 mg/kg). After 150 μL blood samples were collected at 0, 0.5, 1, 2, 4, 6, 8, 10, 12, 24, and 48 h and precipitated with acetonitrile, the plasma concentration of dasatinib was determined through Fluoro- Phenyl column (150 mm×2.1 mm, 3 μm) in a positive ionization mode. The results suggested that ketoconazole, voriconazole, and posaconazole could increase the AUC0-t of dasatinib to varying degrees while significantly reducing its clearance. However, there was no significant impact on the pharmacokinetics of dasatinib, co-administered with itraconazole except for the CL and MRT0-t of dasatinib. Additionally, voriconazole could significantly increase Cmax of dasatinib by approximately 4.12 fold. These data indicated that ketoconazole, posaconazole and voriconazole should be cautiously co-administered with dasatinib or close therapeutic drug monitoring of dasatinib concentration, which might cause the drug-drug interaction.