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.

Flux balance analysis predicts Warburg-like effects of mouse hepatocyte deficient in miR-122a.

The liver is a vital organ involving in various major metabolic functions in human body. MicroRNA-122 (miR-122) plays an important role in the regulation of liver metabolism, but its intrinsic physiological functions require further clarification. This study integrated the genome-scale metabolic model of hepatocytes and mouse experimental data with germline deletion of Mir122a (Mir122a-/-) to infer Warburg-like effects. Elevated expression of MiR-122a target genes in Mir122a-/-mice, especially those encoding for metabolic enzymes, was applied to analyze the flux distributions of the genome-scale metabolic model in normal and deficient states. By definition of the similarity ratio, we compared the flux fold change of the genome-scale metabolic model computational results and metabolomic profiling data measured through a liquid-chromatography with mass spectrometer, respectively, for hepatocytes of 2-month-old mice in normal and deficient states. The Ddc gene demonstrated the highest similarity ratio of 95% to the biological hypothesis of the Warburg effect, and similarity of 75% to the experimental observation. We also used 2, 6, and 11 months of mir-122 knockout mice liver cell to examined the expression pattern of DDC in the knockout mice livers to show upregulated profiles of DDC from the data. Furthermore, through a bioinformatics (LINCS program) prediction, BTK inhibitors and withaferin A could downregulate DDC expression, suggesting that such drugs could potentially alter the early events of metabolomics of liver cancer cells.

Matrine attenuates allergic airway inflammation and eosinophil infiltration by suppressing eotaxin and Th2 cytokine production in asthmatic mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Matrine has been isolated from Sophora flavescens, and found to show anti-inflammatory effects in macrophages and anti-cachectic effects in hepatomas. The present study investigated whether matrine suppressed eosinophil infiltration and airway hyperresponsiveness (AHR) in mice, and decreased the inflammatory response of tracheal epithelial cells. MATERIALS AND METHODS: BALB/c mice were sensitized and challenged with ovalbumin to induce allergic asthma in mice. These asthmatic mice were given various doses of matrine by intraperitoneal injection. Additionally, activated human tracheal epithelial cells (BEAS-2B cells) were treated with matrine, and evaluated for levels of proinflammatory cytokines and chemokines. RESULTS: We found that matrine significantly decreased AHR, and suppressed goblet cell hyperplasia, eosinophil infiltration, and inflammatory response in the lung tissue of asthmatic mice. Matrine also reduced the levels of Th2 cytokines and chemokines in bronchoalveolar lavage fluid, and suppressed OVA-IgE production in serum. Furthermore, matrine treatment of activated BEAS-2B cells decreased production of proinflammatory cytokines and eotaxins, as well as suppressed ICAM-1 expression and thus adhesion of eosinophils to inflammatory BEAS-2B cells in vitro. CONCLUSIONS: Our findings suggest that matrine can improve allergic asthma in mice, and therefore has potential therapeutic potential in humans.