Crizotinib (CRIZO) has been widely employed to treat non‐small‐cell lung cancer. However, hepatic inflammatory injury is the major toxicity of CRIZO, which limits its clinical application, and the underlying mechanism of CRIZO‐induced hepatotoxicity has not been fully explored. Herein, we used cell counting kit‐8 assay and flow cytometry to detect CRIZO‐induced cytotoxicity on human hepatocytes (HL‐7702). CRIZO significantly reduced the survival rate of hepatocytes in a dose‐dependent manner. Furthermore, the reactive oxygen species (ROS) assay kit showed that CRIZO treatment strongly increased the level of ROS. In addition, CRIZO treatment caused the appearance of balloon‐like bubbles and autophagosomes in HL‐7702 cells. Subsequently, Western blotting, quantitative real‐time PCR and ELISA assays revealed that ROS‐mediated pyroptosis and autophagy contributed to CRIZO‐induced hepatic injury. Based on the role of ROS in CRIZO‐induced hepatotoxicity, magnesium isoglycyrrhizinate (MgIG) was used as an intervention drug. MgIG activated the Nrf2/HO‐1 signalling pathway and reduced ROS level. Additionally, MgIG suppressed hepatic inflammation by inhibiting NF‐κB activity, thereby reducing CRIZO‐induced hepatotoxicity. In conclusion, CRIZO promoted autophagy activation and pyroptosis via the accumulation of ROS in HL‐7702 cells. MgIG exerts therapeutic effects on CRIZO‐induced hepatotoxicity by decreasing the level of ROS.

Objectives: The objective of this study was to investigate the possible interaction of shikonin and β,β-dimethylacrylshikonin (DSK) with tramadol. Methods: Human liver microsome (HLM) and rat liver microsome (RLM) incubation experiments were carried out to assess the half-maximal inhibitory concentration (IC50) and inhibitory mechanism of shikonin and DSK on tramadol metabolism in vitro. And pharmacokinetics experiments containing low and high doses of shikonin and DSK were performed to confirm the inhibitory effects on tramadol metabolism in vivo. Key findings: The IC50 of shikonin on tramadol metabolism was 5.66 ± 1.2 μmol/l in HLM and 3.35 ± 1.1 μmol/l in RLM, while that of DSK on tramadol metabolism was 14.33 ± 1.1 μmol/l in HLM and 8.24 ± 1.26 μmol/l in RLM. Moreover, shikonin and DSK showed non-competitive inhibition of the cytochrome P450 enzyme in both HLM and RLM. Oral administration of 10 and 30 mg/kg shikonin inhibited tramadol metabolism in a dose-dependent manner. Furthermore, a dose of 30 mg/kg DSK inhibited the metabolism of tramadol in rats, while the lower dose of 10 mg/kg showed no inhibitory effect. Conclusions: The results of this study suggest that shikonin and DSK can inhibit tramadol metabolism both in vitro and in vivo.

Aim: Our study is to investigate the effects of triazole antifungal drugs on the pharmacokinetics of lorlatinib in rats. Methods: The samples were precipitated with methanol. Chromatographic separation was performed on a ultra-performance liquid chromatography (UPLC) system using a BEH C18 column. The mobile phase consisted of 0.1% formic acid water and methanol. Lorlatinib and crizotinib (internal standard) were detected in multiple reaction monitoring mode. The fragment ions were 407.3–228.07 for lorlatinib and m/z 450.3–260.0 for crizotinib. Lorlatinib and different triazole antifungal drugs were given to Sprague Dawley rats by gavage, and blood was collected from the tail vein at a certain time point. The validated UPLC–MS/MS method was applied to a drug interaction study of ketoconazole, voriconazole, itraconazole, and posaconazole with lorlatinib in rats. Results: Ketoconazole and voriconazole significantly inhibited lorlatinib metabolism. When administration with ketoconazole and voriconazole, the area under the curve from time zero to infinity of lorlatinib increased by 49.0% and 104.3%, respectively; the clearance decreased by 40.0% and 40.0%, respectively. While itraconazole and posaconazole did not affect lorlatinib pharmacokinetics. Conclusion: The UPLC-MS/MS-based assay is helpful to further understand the pharmacokinetics of lorlatinib in rats, and confirmed the findings that the combination of lorlatinib with CYP3A inhibitors should be avoided as predicted by our pre-clinical studies.