3.1. Effects of high-altitude hypoxia on drug metabolism
The effect of hypoxia on CYP directly leads to changes in drug metabolism kinetics. Acetazolamide is the only drug approved by the US FDA for the prevention and treatment of acute altitude sickness. The clearance (CL) of acetazolamide substantially increased in the plateau environment, especially in acute hypoxia; the apparent volume of distribution (Vz/F), mean residence time (MRT), and degree of protein binding substantially decreased; and the concentration of free acetazolamide in the chronic hypoxia group was substantially lower than that in the low-altitude group, indicating that acetazolamide metabolism was decreased under hypoxia (Ritschel et al., 1998). Dexamethasone can serve as a substitute for acetazolamide in the prevention and treatment of acute altitude sickness. Gong et al. found that the half-life (t1/2 ) and MRT of dexamethasone were substantially prolonged, and the peak concentration (Cmax ) and terminal elimination rate constant (Ke ) were substantially decreased in acute hypoxia, suggesting that dexamethasone elimination decreased under acute hypoxia (Gong et al., 2015). In addition, ibuprofen and acetaminophen, commonly used to treat high altitude headaches, and nifedipine and sildenafil, commonly used to treat pulmonary edema, their pharmacokinetics are similarly altered in a plateau environment (Gola et al., 2016; Gola et al., 2013; Zhu et al., 2022; Zhu et al., 2021). In addition to some acute plateau illnesses, respiratory, central nervous system, and cardiovascular diseases continue to occur frequently. The pharmacokinetic characteristics of over 40 drugs are altered in the hypoxic environment of the plateau, affecting their therapeutic efficacy (Table 2). The majority of these drugs mainly manifest as substantial prolongation of t1/2 and MRT, a substantial increase in the area under curve (AUC), and a substantial decrease in CL, suggesting that the metabolism and CL of most of these drugs are decreased in the hypoxic environment, and that the dosing regimen in the plateau environment needs to be reassessed.