Abstract
The pharmacokinetic characteristics of drugs were altered under high altitude hypoxia, thereby affecting the absorption, distribution, metabolism, and excretion of drug. However, there are few literatures on the pharmacokinetic changes of antipyretic and pain-relieving drugs and cardiovascular system drugs at high altitude. This study aimed to evaluate the pharmacokinetics of acetaminophen and metformin hydrochloride in rats under simulated high altitude hypoxia condition. Mechanically, the protein and mRNA expression of uridine diphosphate glucuronyltransferase 1A1 (UGT1A1) and organic cation transporter 2 (OCT2) were investigated by enzyme linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. Compared with the normoxia group, the t1/2 and AUC of acetaminophen were significantly increased, and the CL/F was significantly decreased in rats after exposure to simulated high altitude hypoxia. The t1/2 of metformin hydrochloride was significantly increased by simulated high altitude hypoxia. No significant differences in AUC and CL/F of metformin hydrochloride were observed when comparing the hypoxia group with the normoxia group. The protein and mRNA expression of UGT1A1 and OCT2 were decreased significantly under hypoxia in rats. This study found obvious changes in the pharmacokinetics of acetaminophen and metformin hydrochloride in rats after exposure to simulated high altitude hypoxia, and they might be due to significant decreases in the expressions of UGT1A1 and OCT2. To sum up, our data suggested that the pharmacokinetics of acetaminophen and metformin hydrochloride should be reexamined, and the optimal dose should be reassessed under hypoxia exposure.
Highlights
The environmental characteristics of high altitude is featured by hypoxia, low pressure, low temperature, dry air, strong wind, and strong ultraviolet radiation, in which hypoxia plays a major role in affecting the activity of human life (Li J. et al, 2015)
The pharmacokinetic parameters of t1/2 and clearance rate (CL)/F found in rats at low altitude were consistent with those reported in 1989, a pharmacokinetic study of acetaminophen (Tarloff et al, FIGURE 3 | Mean plasma concentration time curve for oral acetaminophen (105 mg/kg) for rats after exposure to simulated high altitude hypoxia (N 8)
The pharmacokinetic parameters CL/F of metformin hydrochloride were in accordance with previous study, while the t1/2 observed in our study was about 50% lower (Choi et al, 2010)
Summary
The environmental characteristics of high altitude is featured by hypoxia, low pressure, low temperature, dry air, strong wind, and strong ultraviolet radiation, in which hypoxia plays a major role in affecting the activity of human life (Li J. et al, 2015). Studies have demonstrated the pharmacokinetic differences of drugs such as Lidocaine hydrochloride (Zhang et al, 2016), sulfamethoxazole (Li et al, 2011; Li et al, 2009), lithium (Arancibia et al, 2003), propranolol (Li J. et al, 2015), metoprolol (Zhang et al, 2014), and ibuprofen (Gola et al, 2013; Gola et al, 2016) at high altitudes These studies indicated that the metabolism of most drugs under the high altitude hypoxia environment slowed down, and mean residence time (MRT), half-life time (t1/2) and area under the drug-time curve (AUC) was increased, and clearance rate (CL) was reduced. The research on the effects of hypoxia on drug metabolism is mainly concentrated on the prevention and treatment of high altitude disease drugs, while few literatures on the pharmacokinetic changes of antipyretic and pain-relieving drugs and cardiovascular system drugs under hypoxic conditions was reported
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