Alterations in the hepatic drug-metabolizing enzyme network of mice induced by +Gz exposure and its impact on the pharmacokinetics and pharmacodynamics of modafinil.

BACKGROUND: In aviation and aerospace missions, personnel and astronauts are subjected to brief episodes of +Gz acceleration, resulting in overload stress that adversely affects the cardiovascular, respiratory, and nervous systems. This mechanical stress disrupts hemodynamic balance, tissue oxygenation, and physiological homeostasis. Increasing evidence links this stressor to hepatic injury; as the primary organ for drug metabolism, liver dysfunction may alter the expression and activity of drug-metabolizing enzymes and the pharmacokinetic profiles of circadian rhythm-regulating medications, such as modafinil. This study systematically evaluates the effects of repeated brief + Gz exposure on hepatic drug-metabolizing enzymes and modafinil pharmacokinetics using a murine model. METHODS: A mouse model was established using a 7-day continuous +15 Gz exposure regimen. The anti-fatigue effect of modafinil under + Gz and sleep deprivation conditions was assessed using the Morris water maze. Modafinil plasma concentration was analyzed by ultra-high-performance liquid chromatography (UHPLC) to determine pharmacokinetic parameters. Transcriptomic sequencing, RT-qPCR, Western blot, and enzyme activity assays were employed to comprehensively evaluate the expression of hepatic drug metabolism-related genes and the expression/activity of the key enzyme Cyp3a11. RESULTS: +Gz exposure impaired spatial learning and memory in mice, showing a synergistic negative effect with 24-h sleep deprivation. Modafinil intervention significantly ameliorated these cognitive deficits, indicating retained anti-fatigue efficacy under acceleration stress. +Gz exposure induced mild hepatic dysfunction (elevated ALT/AST). Pharmacokinetic analysis revealed a reduced peak plasma concentration (Cmax), along with significantly prolonged mean residence time (MRT) and elimination half-life (t1/2z) of modafinil in the +Gz group, characterizing a pattern of "delayed absorption-impaired clearance". Transcriptomic analysis showed that + Gz exposure significantly downregulated the transporter Slc17a9 and Ugt2b37, while upregulating Slc25a34/Slc25a47, Abcg5/Abcg8, and the metabolizing enzymes Cyp2b10 and Cyp2c38. Modafinil partially reversed these alterations. The key finding was that + Gz exposure did not alter the mRNA or protein expression levels of Cyp3a11, the principal enzyme responsible for modafinil metabolism, but significantly suppressed its enzymatic activity. CONCLUSION: Brief repeated + Gz stress reprograms the hepatic drug-metabolizing gene expression profile, potentially affecting the metabolism of various drugs in the unique conditions of aerospace environments. Importantly, it functionally inhibits the activity of the key metabolic enzyme Cyp3a11, without altering its expression, resulting in characteristic changes in modafinil pharmacokinetics.