Influences of Magnesium Isoglycyrrhizinate on the Pharmacokinetics of Almonertinib in Rats and Its Potential Mechanisms

Almonertinib has been approved for the first-line therapy of advanced epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). As a hepatoprotective agent, magnesium isoglycyrrhizinate (MgIG) was widely used in the treatment of drug-induced liver injury. Although Almonertinib is commonly prescribed in combination with MgIG in clinical application, the interaction research between them has not been reported. This research was conducted to explore the influences of MgIG on the pharmacokinetics of Almonertinib in rats and to investigate its possible molecular mechanisms. The plasma concentration of Almonertinib in male Sprague-Dawley (SD) rats was determined by ultra-performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS), the messenger RNA (mRNA) and protein expression levels of CYP3A1 (homologous to human CYP3A4) and P-glycoprotein (P-gp) in rat livers were measured by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot analyses. MgIG increased systemic exposure of Almonertinib significantly, resulting in increased AUC_0-t, AUC_0-∞, C_max, and t_1/2, and decreased CL_z. Furthermore, MgIG can markedly down-regulate the expression levels of CYP3A1 and P-gp in rat livers. There is a drug-drug interaction (DDI) between MgIG and almonertinib, which leads to an increase of systemic exposure for almonertinib. Meanwhile, CYP3A1 and P-gp in the liver may be the primary targets of mediating the DDI, but further clinical trials are needed to confirm these results.