UPLC-MS/MS Measurement of the Effect of Isavuconazole, Itraconazole and Fluconazole on the Pharmacokinetics of Selinexor in Rats.

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 Cmax, AUC(0-t) and AUC(0-∞) of selinexor in group B increased by 59.05%, 31.69%, and 31.45%; the Cmax, AUC(0-t) and AUC(0-∞) of selinexor in group C increased by 56.14%, 25.34%, and 25.08%; the Cmax, AUC(0-t) and AUC(0-∞) of selinexor in group D increased by 43.44%, 29.16%, and 31.96%, respectively. The Tmax 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.

[Heavy Metal Contamination of Soils and Crops near a Zinc Smelter].

To evaluate the influence of mining activities on heavy metal contamination and health risks in a zinc-smelting area in Guizhou Province, Pb, Cd, Zn, and Cu in agriculture soils and dominant crops were monitored and analyzed. A single factor pollution index and a comprehensive pollution index were calculated to assess the quality of soils and crops. Furthermore, the potential ecological risks of the four heavy metals in soils and crops were evaluated using the potential ecological risk index (RI). The potential health risks to adults and children induced by the intake of these heavy metals through consumption of crops were evaluated using the hazard quotient (HQ). The results showed that:①The farmlands in the zinc-smelting area were contaminated by heavy metals; the most polluted farm land was corn fields followed by paddy fields and wheat fields. The order of the heavy metal concentrations was Cd > Cu > Zn > Pb. The Nemero index of corn fields was higher than the threshold value of heavy pollution and was higher than that of the paddy and wheat fields. Cd contributed most to the integrated pollution index. ②The very high ecological risk was posed by Cd followed by Pb, Cu, and Zn. The results of the potential ecological risk assessment showed that 1.41% of the sites were classified as low risk, 21.1% classified as medium risk, 35.2% as high risk, and 42.3% as extremely high risk. ③The average concentrations of Pb, Cd, Zn, and Cu in rice were 0.145, 0.017, 16.97, and 2.704 mg·kg-1, respectively. The average concentrations of Pb, Cd, Zn, and Cu in corn were 0.094, 0.055, 26.81, and 4.464 mg·kg-1, respectively. The average concentrations of Pb, Cd, Zn, and Cu in wheat were 0.048, 0.085, 35.37, and 5.426 mg·kg-1, respectively.④Rice, corn, and wheat from the study area were subjected to pollution at different degrees. Among the three crops studied, wheat was polluted most heavily, followed by rice and corn. Contamination levels of rice and corn were safe, whereas the contamination of wheat reached alarming levels. ⑤The daily intake of individual heavy metals from food was below the standard exposure dose set by the United States Environmental Protection Agency. In addition, the assessment results for the comprehensive health risk index for the three crops indicate that the contamination of heavy metals poses health risks to adults and children by food ingestion. ⑥ Positive correlations were not observed between farmlands and crops.