Effects of ketoconazole, voriconazole, and itraconazole on the pharmacokinetics of apatinib in rats.

We investigated the effect of azole antifungal drugs (ketoconazole, voriconazole, and itraconazole) on the pharmacokinetics of apatinib in rats. The rats in ketoconazole, voriconazole, and itraconazole groups received single-dose apatinib 30 mg/kg after the oral administration of ketoconazole, voriconazole, and itraconazole, respectively. Co-administration of ketoconazole or voriconazole significantly increased the apatinib Cmax and AUC(0-t) and decreased the clearance. Co-administration of itraconazole did not significantly affect the pharmacokinetics parameters of apatinib. It could be concluded that both ketoconazole and voriconazole significantly increase the exposure of apatinib, and affect the pharmacokinetics of apatinib in rat. Apatinib can be co-administered with itraconazole, but ketoconazole and voriconazole should be avoided if possible or be underwent therapeutic drug monitoring of apatinib. A further clinical study should be conducted to investigate the inhibitory effect of azole antifungal drugs on the apatinib plasma concentration.

Simultaneous determination of liensinine, isoliensinine and neferine in rat plasma by UPLC-MS/MS and application of the technique to pharmacokinetic studies.

ETHNOPHARMACOLOGICAL RELEVANCE: The in vivo effects of traditional herbal medicines are generally mediated by multiple bioactive components. The main constituents of Lotus Plumule are alkaloids such as liensinine, isoliensinine and neferine. In this study, a simple, sensitive, and robust analytical method based on ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) has been developed for the determination of the three alkaloids in rat plasma using carbamazepine as internal standard (IS). MATERIALS AND METHODS: After precipitation of the proteins with acetonitrile, chromatography was performed on an Acquity UPLC BEH C18 column (2.1mm×50mm, 1.7µm particle size) using a gradient elution with 0.1% formic acid in water and acetonitrile. Mass spectrometry involved positive electrospray ionization and multiple reaction monitoring (MRM) of the transitions at m/z 611.7→206.2 for liensinine, 611.3→192.2 for isoliensinine, 625.2→206.1 for neferine and m/z 237.1→194.2 for IS. RESULTS: The method was linear over the concentration range 5-1000ng/mL with a lower limit of quantifof 5ng/mL for each alkaloid. Inter- and intra-day precision (RSD%) were all within 11.4% and the accuracy (RE%) were equal or lower than 10.4%. Recoveries were more than 75.3% and matrix effects were not significant. Stability studies showed that the three alkaloids were stable under a variety of storage conditions. CONCLUSION: The method was successfully applied to a pharmacokinetic study involving intravenous administration of liensinine, isoliensinine and neferine to rats.