Functional impact of high-altitude hypoxia on central nervous system drug transport: integrated analysis of Blood-brain barrier permeability, drug Transporter/Enzyme expression, and pharmacokinetics

BACKGROUND: The blood-brain barrier is a major obstacle drug transport into the central nervous system. High-altitude hypoxia induces structural and functional alterations in the central nervous system, which in turn can influence drug metabolism and transport throughout the body. METHODS: ) were used as experimental models in this study. The effects of hypoxia on blood-brain barrier structure and function were assessed using Evans Blue staining and confocal laser scanning microscopy. Changes in the expression and activity of drug transporters and drug-metabolizing enzymes under hypoxic conditions were investigated using data-independent acquisition (DIA) proteomic sequencing, RT-qPCR, and western blot. Additionally, pharmacokinetic studies were conducted to evaluate drug concentrations across the blood-brain barrier. RESULTS: High-altitude hypoxic environments significantly altered the cerebral distribution and trans-blood-brain barrier transport of drug substrates by upregulating the expression of the efflux transporter, ATP-binding cassette subfamily B member 1 (Abcb1), downregulating the expression of the drug-metabolizing enzyme CYP2B1, and increasing blood-brain barrier permeability. Moreover, the prolonged half-life (t₁/₂) and reduced total clearance (CL) observed for drug substrates indicate a significant deceleration in their in vivo metabolism under high-altitude hypoxia. CONCLUSION: Our findings preliminarily reveal the differential characteristics of drug metabolism under high-altitude hypoxic environments, implying potential differences in drug disposition between high-altitude and plain human populations. Accordingly, these findings provide novel theoretical insights into the molecular regulatory mechanism of drug metabolism in hypoxic plateau environments, and lay a valuable foundational reference for subsequent basic research on rational drug application in plateau areas.