Objective: An ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the determination of selinexor was established to investigate the effects of isavuconazole, itraconazole and fluconazole on the pharmacokinetics of selinexor in rats, respectively.
Methods: Twenty-four healthy male rats were randomly divided into four groups: group A, normal saline; group B, isavuconazole (20 mg/kg); group C, itraconazole (20 mg/kg); and group D, fluconazole (20 mg/kg). After 30 min of oral administration of normal saline, isavuconazole, itraconazole, and fluconazole, all the rats were given selinexor (8 mg/kg). The plasma concentration of selinexor was estimated by UPLC-MS/MS, and the pharmacokinetic parameters of selinexor were calculated by Drug and Statistics (DAS) 2.0 software.
Results: Under these experimental conditions, the method showed good linearity and stability. Intraday and interday accuracy and sample recovery were acceptable. Compared with group A, the C_max, AUC_(0−t) and AUC_(0−∞) of selinexor in group B increased by 59.05%, 31.69%, and 31.45%; the C_max, AUC_(0−t) and AUC_(0−∞) of selinexor in group C increased by 56.14%, 25.34%, and 25.08%; the C_max, AUC_(0−t) and AUC_(0−∞) of selinexor in group D increased by 43.44%, 29.16%, and 31.96%, respectively. The T_max of the experimental groups were extended, and CLz/F was also significantly reduced.
Conclusion: These results indicated that isavuconazole, itraconazole, and fluconazole have significant inhibitory effects on selinexor pharmacokinetics and increased selinexor plasma exposure in rats. Therefore, when these drugs were used in combination, clinicians should pay attention to the changes in treatment effects and the occurrence of adverse reactions caused by the drug-drug interactions.
Keywords: isavuconazole, itraconazole, fluconazole, selinexor, UPLC-MS/MS, pharmacokinetics, drug-drug interactions