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.