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 Rats and human brain microvascular endothelial cells (hCMEC/D 3 ) 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.