Metabolic Characteristics of Schisantherin B in Mice with Metabolic-Associated Fatty Liver Disease

<b>Objectives</b>: We aimed to observe the pharmacokinetic differences of schisantherin B (STB) in the blood and liver of normal and metabolic-associated fatty liver disease (MAFLD) mice, as well as the changes in CYP450 enzymes in MAFLD mice. <b>Methods</b>: A MAFLD model was established in C57 mice fed a high-fat diet. Blood and liver samples from mice administered STB (5 mg/kg) were analyzed by high-performance liquid chromatography-electrospray tandem mass spectrometry (HPLC-ESI-MS) to identify major metabolites of STB and assess the activity of CYP450 enzymes. Pharmacokinetic parameters were calculated using DAS 3.0 software. The cocktail assay method was employed to determine CYP450 enzyme activity in hepatocytes in vitro. <b>Results</b>: The activities of CYP1A2, CYP2B6, CYP2C9, and CYP3A4 were significantly decreased, while the CYP2E1 activity was significantly increased in MAFLD hepatocyte model. In vitro liver microsomal experiments revealed that STB was primarily metabolized by CYP3A4 and CYP2C9. Compared to normal mice, STB in the liver tissue of MAFLD mice showed a significantly reduced area under the curve (<i>AUC</i>) and peak concentration (<i>C_max</i>), prolonged half-life (<i>t</i>_1/2), decreased mean retention time (<i>MRT</i>), and increased clearance (<i>CL</i>). In contrast, the <i>AUC</i>, <i>C_max</i>, and <i>t</i>_1/2 of STB in the serum of MAFLD mice were significantly increased, while the <i>CL</i> was decreased. <b>Conclusions</b>: Changes in the activity of liver microsomal enzymes following fatty liver injuries in MAFLD mice may lead to pharmacokinetic differences in STB, thereby affecting its metabolism in the liver.