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. 2021 Jun 18:12:692349.
doi: 10.3389/fphar.2021.692349. eCollection 2021.

Pharmacokinetics of Acetaminophen and Metformin Hydrochloride in Rats After Exposure to Simulated High Altitude Hypoxia

Jun-Bo Zhu  1   2 , Jian-Xin Yang  1   2 , Yong-Qiong Nian  3 , Gui-Qin Liu  4 , Ya-Bin Duan  1 , Xue Bai  1 , Qian Wang  1 , Yang Zhou  1 , Xue-Jun Wang  5 , Ning Qu  6 , Xiang-Yang Li  2
Affiliations

Pharmacokinetics of Acetaminophen and Metformin Hydrochloride in Rats After Exposure to Simulated High Altitude Hypoxia

Jun-Bo Zhu et al. Front Pharmacol. .

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.

Keywords: OCT2; UGT1A1; acetaminophen; high altitude hypoxia; metformin hydrochloride; pharmacokinetics.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Changes in red blood cells, white blood cells, hemoglobin, lymphocytes, granulocytes, and platelets in the rats after exposure to simulated high altitude hypoxia. The data are presented as mean ± SD. N = 8. The data were analyzed using ANOVA, and the differences between the means of two groups were compared using LSD tests. * p < 0.05, **p < 0.01 compared to the normoxia group; # p < 0.05, ## p < 0.01 compared to the acute hypoxia group.
FIGURE 2
FIGURE 2
Changes in ScO2, alanine aminotransferase, aspartate aminotransferase, total bilirubin, total protein, albumin, glutamate, total cholesterol, and globulin in the rats after exposure to simulated high altitude hypoxia. The data are presented as mean ± SD. N = 8. The data were analyzed using ANOVA, and the differences between the means of two groups were compared using LSD tests. * p < 0.05, **p < 0.01 compared to the normoxia group; # p < 0.05, ## p < 0.01 compared to the acute hypoxia group.
FIGURE 3
FIGURE 3
Mean plasma concentration time curve for oral acetaminophen (105 mg/kg) for rats after exposure to simulated high altitude hypoxia (N = 8).
FIGURE 4
FIGURE 4
Mean plasma concentration time curve for oral metformin hydrochloride (45 mg/kg) for rats after exposure to simulated high altitude hypoxia (N = 8).
FIGURE 5
FIGURE 5
Protein expression of UGT1A1 in rats after exposure to simulated high altitude hypoxia. The data are presented as mean ± SD. N = 6. The data were analyzed using ANOVA, and the differences between the means of two groups were compared using LSD tests. **p < 0.01 compared to the normoxia group.
FIGURE 6
FIGURE 6
Protein expression of OCT2 in rats after exposure to simulated high altitude hypoxia. The data are presented as mean ± SD. N = 6. The data were analyzed using ANOVA, and the differences between the means of two groups were compared using LSD tests. **p < 0.01 compared to the normoxia group; # p < 0.05 compared to the acute hypoxia group.
FIGURE 7
FIGURE 7
The mRNA expression of UGT1A1 in rats after exposure to simulated high altitude hypoxia. The data are presented as mean ± SD. N = 6. The data were analyzed using ANOVA, and the differences between the means of two groups were compared using LSD tests. *p < 0.05 compared to the normoxia group.
FIGURE 8
FIGURE 8
The mRNA expression of OCT2 in rats after exposure to simulated high altitude hypoxia. The data are presented as mean ± SD. N = 6. The data were analyzed using ANOVA, and the differences between the means of two groups were compared using LSD tests.
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