In the current research experiment, a sensitive, precise and rapid bioanalytical approach involving the detection of fedratinib concentrations in rat plasma by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) technique was optimized and established, and it was employed to describe the changes of fedratinib concentrations after oral treatment with various antifungal drugs (isavuconazole, posaconazole, fluconazole and itraconazole). An Acquity UPLC BEH reverse-phase C18 column (2.1 mm × 50 mm, 1.7 μm) was used for chromatographic separation of fedratinib and bosutinib (as internal standard (IS) in our study) under a linear gradient elution of the mobile phase, which was composed of solution A (acetonitrile) and solution B (water with 0.1% formic acid), along with 0.40 ml/min flow rate. The analyte and internal standard were measured with electrospray ion source in positive ion mode on a XEVO TQS triple quadrupole tandem mass spectrometer. The newly developed UPLC-MS/MS assay displayed enough linearity within the concentration range of 0.5–500 ng/ml for calibration curve. The intra- and inter-day of precision and accuracy were evaluated and validated to meet the requirements for the guidelines of bioanalytical assay. In addition, the findings of matrix effect, recovery, and stability were all within the acceptable limits. The new UPLC-MS/MS method was also successfully applied to characterize the pharmacokinetic changes of fedratinib in rats in the present of different antifungal drugs (such as isavuconazole, posaconazole, fluconazole and itraconazole). It turned out that fluconazole resulted in a prominent inhibitory effect on fedratinib metabolism in rats, followed by treatment with itraconazole and isavuconazole. Therefore, the toxicity of fedratinib should be avoided when the concurrent use of fedratinib with CYP3A4 inhibitors may occur.

Several mechanisms underlying nephrolithiasis, one of the most common urological diseases, involve calcium oxalate formation, including oxidative stress, inflammatory reactions, fibrosis, pyroptosis, and apoptosis.

Background and Aim: Dasatinib is approved for the treatment of leukaemia worldwide. Triazole agents such as posaconazole may be used for the control of secondary fungal infection with leukaemia. This work aimed to develop a bioanalytical method to study the potential interaction between dasatinib and posaconazole. Methods: An ultrahigh-performance liquid chromatography-tandem mass spectrometry method was established to measure the plasma concentrations of dasatinib and posaconazole in rats simultaneously. Simple protein precipitation with acetonitrile was applied to extract dasatinib and posaconazole in samples. The chromatographic separation of analytes was conducted on an UPLC BEH C18 column using a mobile phase consisting of 0.1% aqueous formic acid and acetonitrile. Dasatinib and posaconazole were monitored in positive ion mode with the following mass transition pairs: m/z 488.2→ 401.1 for dasatinib and m/z 701.3→ 683.4 for posaconazole. The method was successfully applied for pharmacokinetic interaction between dasatinib and posaconazole. Results: The established method expressed good linearity in 1– 1000 ng/mL of dasatinib and 5– 5000 ng/mL of posaconazole, with limit of detection was 1 ng/mL and 5 ng/mL, respectively. Methodology validations, including accuracy, precision, matrix effect, recovery, and stability, met the US Food and Drug Administration (FDA) acceptance criteria for bioanalytical method validation. Dasatinib strongly inhibited the clearance of posaconazole in vivo, while posaconazole expressed no significant effect on the pharmacokinetics of dasatinib. Conclusion: Dasatinib alters the pharmacokinetics of posaconazole. Attention should be paid to the unexpected risk of adverse clinical outcomes when posaconazole is co-administered with dasatinib.