Disinfection by-products of metformin in the environment: A systematic toxicity evaluation on gut-liver-brain axis homeostasis and establishment of a detection method based on NiFe-LDOs/N-BC composite

Jiaqi Wang; Chunwang Fu; Guihong Zhang; Changlan Chen; Xin Wang; Yang Wang; Yangcheng Liu; Zheng Xiang

doi:10.1016/j.watres.2024.122895

Disinfection by-products of metformin in the environment: A systematic toxicity evaluation on gut-liver-brain axis homeostasis and establishment of a detection method based on NiFe-LDOs/N-BC composite

Water Res. 2024 Dec 4:272:122895. doi: 10.1016/j.watres.2024.122895. Online ahead of print.

Authors

Jiaqi Wang¹, Chunwang Fu², Guihong Zhang¹, Changlan Chen¹, Xin Wang¹, Yang Wang³, Yangcheng Liu⁴, Zheng Xiang⁵

Affiliations

¹ School of Pharmaceutical Science, Liaoning University, Shenyang 110036, China.
² Shenyang Xingqi Pharmaceutical Co., Ltd., Shenyang 110163, China.
³ School of Pharmaceutical Science, Liaoning University, Shenyang 110036, China. Electronic address: wy519785091@163.com.
⁴ School of Pharmaceutical Science, Liaoning University, Shenyang 110036, China. Electronic address: liu_yangcheng@outlook.com.
⁵ School of Pharmaceutical Science, Liaoning University, Shenyang 110036, China; Shenyang Key Laboratory for Causes and Drug Discovery of Chronic Diseases, Shenyang Anning Hospital, Shenyang 110000, China. Electronic address: rainbowaftersnow@hotmail.com.

PMID: 39644686
DOI: 10.1016/j.watres.2024.122895

Abstract

Metformin, a first-line drug used to treat type 2 diabetes, is not metabolised in the body and discharged into the environment in the form of prototype drugs. Compounds C (C₄H₆ClN₃) and Y (C₄H₆ClN₅) are the main disinfection byproducts of metformin in urban sewage treatment; however, their potential toxicity is unclear. In this study, absorption, distribution, metabolism, elimination, and toxicity (ADMET) prediction indicated that compounds C and Y had potential hepatotoxicity and could cross the blood-brain-barrier. Toxicity verification tests indicated a sex difference in the acute toxicity of compound C, with an LD₅₀ value of 253.269 mg kg^-1 for male mice and 728.908 mg kg^-1 for female mice. The subacute toxicity of compounds C and Y was evaluated to study the toxicity mechanism via the gut-liver-brain axis, which indicated that they could cause damage to the liver and brain, change the composition of the gut microbiota, and disturb the levels of metabolites in mice. Neuron-like magnetic N-doped biochar (NiFe-LDOs/N-BC) was synthesised using hydrothermal and calcination methods, and the optimised d-MSPE-HPLC-UV method was proven to be applicable for the trace detection of compound C in real water samples. The simultaneous presentation of toxicity evaluation and trace detection of compound C is intended to make the monitoring system for compound C more comprehensive.

Keywords: Biochar; Disinfection by-products; Gut-liver-brain axis; Metformin; Sub-acute toxicity; d-MSPE.