Pharmacokinetics of Midazolam in Plasma and Brain Tissue of Rats after Exposure to Acute and Chronic High Altitude Hypoxia.

Tian, Lu, Guiqin Liu, Qin Zhao, Junjun Han, Yue Lin, Wang, Jia, Delong Duo, Duan Yabin, Zhu Junbo, and Li Xiangyang. Pharmacokinetics of midazolam in plasma and brain tissue of rats after exposure to acute and chronic high altitude hypoxia. High Alt Med Biol. 00:00-00, 2025. Background: Midazolam effectively improves sleep quality under high altitude hypoxia by reducing central nervous system excitability. Methods: Field modeling and sample collection were performed at an altitude of 4,300 m in a high altitude hypoxic environment with a pressure of inspired oxygen of 107 mmHg. Pharmacokinetic alterations of midazolam in high altitude hypoxic rats are determined by high performance liquid chromatography-mass spectrometry. Quantitative real-time polymerase chain reaction and Western blot were used to confirm the connection with drug metabolism and alterations in hypoxia CYP3A4 and P-glycoprotein (P-gp) expression. Results: This study demonstrated that high altitude hypoxia increased blood-brain barrier permeability in rats, caused brain tissue damage, and altered the expression of inflammatory cytokines in the brain. In the acute high altitude group and the chronic high altitude group, the area under the curve and T_max of plasma midazolam revealed substantial increases of 88.6% and 283% and 28.6% and 85.3%, respectively. The clearance rate reduced by 47.3% and 90.0%, while the brain-blood drug concentration ratio (C_brain/C_plasma) diminished by 11.4% and 82.1%, respectively. The relative expression of CYP3A1 mRNA in the brain tissue of high altitude rats decreased by 42.4% and 66.8%, respectively, and the protein expression was downregulated, while the relative expression of P-gp mRNA increased by 61.3% and 91.2%, respectively (p < 0.05 for all parameters), and the protein expression was upregulated. High altitude hypoxia altered CYP3A1 and P-gp expression and activity, causing alterations in midazolam metabolism. Conclusions: This research provided a new reference for the rational use of midazolam in highland areas.