Modafinil ameliorates sleep deprivation-induced memory impairment under acute hypobaric hypoxia via biphasic Cyp3a11 regulation and altered pharmacokinetics.

This study aimed to elucidate the dynamic impact of acute hypobaric hypoxia (HH) on the pharmacokinetics of modafinil (MOD) and its association with liver injury and regulation of the key metabolizing enzyme Cyp3a11. A mouse model combining acute HH (simulating 5000 m) with 24 hours sleep deprivation was established. MOD was administered by gavage. Assessments included the Morris water maze test, high-performance liquid chromatography pharmacokinetic analysis, serum alanine aminotransferase/aspartate aminotransferase measurement, hepatic H&E staining, and analysis of Cyp3a11 expression via quantitative reverse transcription polymerase chain reaction, Western blot, and immunohistochemistry assays. HH exacerbated cognitive deficits, which were ameliorated by MOD. It induced biphasic pharmacokinetic alterations: accelerated absorption (higher early plasma concentration) but impeded elimination (increased area under the plasma concentration-time curve, prolonged mean residence time, and decreased apparent clearance). These changes correlated with time-dependent liver responses: after 1 hour HH, alanine aminotransferase/aspartate aminotransferase transiently decreased with compensatory Cyp3a11 upregulation but no significant histopathological damage; after 24 hours HH, progressive liver injury (inflammation, vacuolation, and necrosis) developed alongside significant suppression of Cyp3a11 expression. While MOD retains cognitive-enhancing efficacy under HH, its pharmacokinetics are markedly altered. The shift from accelerated absorption to delayed elimination is closely associated with HH-induced biphasic regulation of hepatic Cyp3a11 and progressive liver injury, indicating a need for optimized dosing strategies in HH scenarios. SIGNIFICANCE STATEMENT: This study reveals how high-altitude hypoxia alters modafinil's pharmacokinetics and efficacy via hepatic Cyp3a11 regulation, offering critical insights for optimizing drug use in hypobaric hypoxia environments.