The Impact of Baohuoside I on the Metabolism of Tofacitinib in Rats.

Purpose: To study the potential drug-drug interactions between tofacitinib and baohuoside I and to provide the scientific basis for rational use of them in clinical practice. Methods: A total of eighteen Sprague-Dawley rats were randomly divided into three groups: control group, single-dose group (receiving a single dose of 20 mg/kg of baohuoside I), and multi-dose group (receiving multiple doses of baohuoside I for 7 days). On the seventh day, each rat was orally administered with 10 mg/kg of tofacitinib 30 minutes after giving baohuoside I or vehicle. Blood samples were collected and determined using UPLC-MS/MS. In vitro effects of baohuoside I on tofacitinib was investigated in rat liver microsomes (RLMs), as well as the underlying mechanism of inhibition. The semi-inhibitory concentration value (IC50) of baohuoside I was subsequently determined and its inhibitory mechanism against tofacitinib was analyzed. Furthermore, the interactions between baohuoside I, tofacitinib and CYP3A4 were explored using Pymol molecular docking simulation. Results: The administration of baohuoside I orally has been observed to enhance the area under the concentration-time curve (AUC) of tofacitinib and decrease the clearance (CL). The observed disparity between the single-dose and multi-dose groups was statistically significant. Furthermore, our findings suggest that the impact of baohuoside I on tofacitinib metabolism may be a mixture of non-competitive and competitive inhibition. Baohuoside I exhibit an interaction with arginine (ARG) at position 106 of the CYP3A4 enzyme through hydrogen bonding, positioning itself closer to the site of action compared to tofacitinib. Conclusion: Our study has demonstrated the presence of drug-drug interactions between baohuoside I and tofacitinib, which may arise upon pre-administration of tofacitinib. Altogether, our data indicated that an interaction existed between tofacitinib and baohuoside I and additional cares might be taken when they were co-administrated in clinic.

Evaluation of the inhibitory effect of azoles on pharmacokinetics of lenvatinib in rats both in vivo and in vitro by UPLC-MS/MS.

BACKGROUND: Lenvatinib is a multitargeted tyrosine kinase inhibitor used in the treatment of a variety of solid tumors. This study aims to investigate the potential pharmacokinetic interactions between lenvatinib and various azoles (ketoconazole, voriconazole, isavuconazole and posaconazole) when orally administered to rats. METHODS: A total of 30 Sprague-Dawley rats were randomly allocated into five groups and administered 20 mg/kg of ketoconazole, voriconazole, isavuconazole and 30 mg/kg of posaconazole and 0.5% CMC-Na, through gavage for a duration of 7 days prior to the commencement of the experiment. On the final day, the rats were given 10 mg/kg of lenvatinib. The blood concentration of lenvatinib was determined using UPLC-MS-MS. In vitro lenvatinib were incubated with azoles and rat liver microsomes (RLMs) or human liver microsomes (HLMs). Molecular docking was lastly used to examine the binding strength of the enzymes and ligands with Autodock Vina. RESULTS: AUC and Cmax of lenvatinib significantly increased with each of the azoles (p < 0.05), whereas CLz/F decreased 0.83-flod, 0.41-fold (p < 0.05) and 0.72-fold (p < 0.01) in voriconazole, isavuconazole and ketoconazole in rats. The IC50 of lenvatinib with the azoles were 0.237, 1.300, 0.355 and 2.403 µM in RLMs and 0.160, 1.933, 3.622 and 1.831 µM in HLMs. Molecular docking analysis suggested that azoles exhibited a strong binding ability towards the target enzymes. CONCLUSION: It is imperative to acknowledge the potential drug-drug interactions mediated by CYP3A4 between azoles and lenvatinib, as these interactions hold significant implications for their clinical utilization.

Effects of bergapten on the pharmacokinetics of macitentan in rats both in vitro and in vivo.

Macitentan was approved by the United States Food and Drug Administration (FDA) in 2013 for the treatment of pulmonary arterial hypertension (PAH). Bergapten is a furanocoumarin that is abundant in Umbelliferae and Rutaceae plants and is widely used in many Chinese medicine prescriptions. Considering the possible combination of these two compounds, this study is aimed to investigate the effects of bergapten on the pharmacokinetics of macitentan both in vitro and in vivo. Rat liver microsomes (RLMs), human liver microsomes (HLMs), and recombinant human CYP3A4 (rCYP3A4) were used to investigate the inhibitory effects and mechanisms of bergapten on macitentan in vitro. In addition, pharmacokinetic parameters were also studied in vivo. Rats were randomly divided into two groups (six rats per group), with or without bergapten (10 mg/kg), and pretreated for 7 days. An oral dose of 20 mg/kg macitentan was administered to each group 30 min after bergapten or 0.5% CMC-Na administration on day 7. Blood was collected from the tail veins, and the plasma concentrations of macitentan and its metabolites were assessed by ultra-performance liquid chromatography - tandem mass spectrometer (UPLC-MS/MS). Finally, we analyzed the binding force of the enzyme and two small ligands by in silico molecular docking to verify the inhibitory effects of bergapten on macitentan. The in vitro results revealed that the IC50 values for RLMs, HLMs, and rCYP3A4 were 3.84, 17.82 and 12.81 µM, respectively. In vivo pharmacokinetic experiments showed that the AUC(0-t), AUC(0-∞), and Cmax of macitentan in the experimental group (20,263.67 µg/L*h, 20,378.31 µg/L*h and 2,999.69 µg/L, respectively) increased significantly compared with the control group (7,873.97 µg/L*h, 7,897.83 µg/L*h and 1,339.44 µg/L, respectively), while the CLz/F (1.07 L/h/kg) of macitentan and the metabolite-parent ratio (MR) displayed a significant decrease. Bergapten competitively inhibited macitentan metabolism in vitro and altered its pharmacokinetic characteristics in vivo. Further molecular docking analysis was also consistent with the experimental results. This study provides a reference for the combined use of bergapten and macitentan in clinical practice.

Inhibitory effect of Schisandrin on the pharmacokinetics of poziotinib in vivo and in vitro by UPLC-MS/MS.

BACKGROUND: As a pan-HER tyrosine kinase inhibitor with a promising application prospect, poziotinib is likely to be coadministered with Schisandrins in clinical treatment due to its anticancer activities. METHODS: Eighteen Sprague-Dawley rats were randomly divided into three groups: Schisandrin A group and Schisandrin B group (20 mg/kg daily for 1 week), and control group (vehicle). On day 8, poziotinib (2 mg/kg) was administered by oral gavage 30 min later. An in vitro study was developed to identify the possible mechanisms of Schisandrins on poziotinib metabolism. All analytes were detected by UPLC/MS-MS, and molecular docking was performed by AutoDock Tools. RESULTS: When rats were preadministered with Schisandrin A, AUC(0-∞) and Cmax of poziotinib were obviously increased by 0.79- and 1.17-fold, whereas the Vz/F and CLz/F values were dramatically decreased. The results in Schisandrin B group presented similarly. Both Schisandrin A and Schisandrin B were mixed inhibitors of poziotinib in RLMs, and Schisandrin B showed stronger inhibitory activity with IC50 values of 2.55 µM for M1 and 6.97 µM for M2. Molecular docking analysis demonstrated that Schisandrin A and Schisandrin B exhibited a strong binding ability towards CYP2D6 as compared to CYP3A4. CONCLUSION: All results provided the direct evidence of the pharmacokinetic drug-drug interactions (DDIs) between Schisandrin and poziotinib. Thus, particular attention should be paid when poziotinib is taken together with Schisandrins in clinical practice.

The role of iron homeostasis and iron-mediated ROS in cancer.

As an important trace element, iron plays an essential role in many biology processes like cell proliferation, metabolism, and mitochondrial function. However, the disruption of iron homeostasis tends to cells death and human diseases due to it servers as mediator to promote the production of reactive oxygen species (ROS). In this review, first we introduced the mechanism of complex iron-mediated ROS involved in apoptosis, necroptosis, ferroptosis and pyroptosis. Next, we discussed the controversial role of excess iron and iron deficiency in tumor. Finally, we discussed the anti-cancer effects of iron on both sides, and novel iron-related strategies. This review outlined the mechanisms and regulation of iron homeostasis and iron-mediated ROS in tumors, and discussed the iron-related treatments.

The role of long non-coding RNAs in mediating chemoresistance by modulating autophagy in cancer.

Cancer is a complex process in which protein-coding and non-coding genes play essential roles. Long noncoding RNAs (lncRNAs), as a subclass of noncoding genes, are implicated in various cancer processes including growth, proliferation, metastasis, and angiogenesis. Due to presence in body fluids such as blood and urine, lncRNAs have become novel biomarkers in cancer detection, diagnosis, progression, and therapy response. Remarkably, increasing evidence has verified that lncRNAs play essential roles in chemoresistance by targeting different signalling pathways. Autophagy, a highly conserved process in response to environmental stresses such as starvation and hypoxia, plays a paradoxical role in inducing resistance or sensitivity to chemotherapy agents. In this regard, we reviewed chemoresistance, the role of lncRNAs in cancer, and the role of lncRNAs in chemoresistance by modulating autophagy.