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

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.

High-altitude Hypoxia Influences the Activities of the Drug-Metabolizing Enzyme CYP3A1 and the Pharmacokinetics of Four Cardiovascular System Drugs

“…As one of the body’s defense systems against foreign bodies, white blood cell count can reflect the immune status of the body. The results of the present study indicated an increase in the white blood cell count of rats in both the acute and chronic hypoxia groups, indicating that hypoxic conditions may induce inflammatory responses, which was inconsistent with a previous finding [ 43 ] that reported a decrease in the white blood cell count of rats in a hypoxic environment. The differences in results could be attributed to differences in study methodology, hypoxia modeling method, modeling time of rats, and the noncontinuous hypoxia state and hypoxia time caused by the need for animal treatment during the simulated hypoxia modeling period.…”

Physiological adaptations affecting drug pharmacokinetics in space: what do we really know? A critical review of the literature

“…Recently, changes in the PK of acetaminophen and metformin hydrochloride have been observed in rats under simulated high altitude hypoxic conditions. These modifications were driven by a significant decrease in the transcription of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and organic cation transporter 2 (OCT2) (Zhu et al, 2021). A fine control of the major liver enzymes, or the levels of circulating metabolites of drugs with a low therapeutic index, is therefore mandatory for the definition of safe and effective therapy.…”

Space medicine: Hunting for pharmacologist's guide in dealing with drugs in microgravity

“…Simulated high-altitude hypoxic conditions revealed a decline in the transcription of organic cation transporter 2 and uridine diphosphate glucuronosyltransferase 1A1 leading to changes in the pharmacokinetics of metformin and acetaminophen. [ 44 ] Additional evidence is required about identified genes and enzymes, particularly the ones involved in metabolizing common drugs used in spaceflight. In addition, one has to focus on drug-drug and drug-diet interactions in spaceflight.…”