Metformin Contamination in Global Waters: Biotic and Abiotic Transformation, Byproduct Generation and Toxicity, and Evaluation as a Pharmaceutical Indicator

Abstract

Metformin is the first-line antidiabetic drug and one of the most prescribed medications worldwide. Because of its ubiquitous occurrence in global waters and demonstrated ecotoxicity, metformin, as with other pharmaceuticals, has become a concerning emerging contaminant. Metformin is subject to transformation, producing numerous problematic transformation byproducts (TPs). The occurrence, removal, and toxicity of metformin have been continually reviewed; yet, a comprehensive analysis of its transformation pathways, byproduct generation, and the associated change in adverse effects is lacking. In this review, we provide a critical overview of the transformation fate of metformin during water treatments and natural processes and compile the 32 organic TPs generated from biotic and abiotic pathways. These TPs occur in aquatic systems worldwide along with metformin. Enhanced toxicity of several TPs compared to metformin has been demonstrated through organism tests and necessitates the development of complete mineralization techniques for metformin and more attention on TP monitoring. We also assess the potential of metformin to indicate overall contamination of pharmaceuticals in aquatic environments, and compared to the previously acknowledged ones, metformin is found to be a more robust or comparable indicator of such overall pharmaceutical contamination. In addition, we provide insightful avenues for future research on metformin.

Metformin: update on mechanisms of action and repurposing potential

“…Based on the large volumes of metformin excreted unchanged in urine, metformin can be regarded as a prominent emerging water pollutant. The presence of metformin in the influents of wastewater treatment plants (WWTPs) has been used as an indicator of pharmacological contamination and in wastewater-based epidemiology studies to assess metformin consumption in populations 231 , 232 . Due to its low removal rate in most conventional WWTPs, metformin is consistently detected with concentrations ranging from nanograms to micrograms per litre in effluents of WWTPs, surface waters and even drinking water 233 , 234 .…”

“…Due to its low removal rate in most conventional WWTPs, metformin is consistently detected with concentrations ranging from nanograms to micrograms per litre in effluents of WWTPs, surface waters and even drinking water 233 , 234 . The widespread occurrence of this compound and its numerous organic transformation products generated via microbial degradation and photolysis (for example, guanylurea and C 2 N 4 H 6 O) in the aquatic environment poses a global threat to environmental health 232 , 235 , 236 . The bioaccumulation of these contaminants in aquatic animals and plants has been extensively documented 233 , 235 .…”

Aerobic Degradation of the Antidiabetic Drug Metformin by Aminobacter sp. Strain NyZ550

“…2,10,12,13 It has recently been categorized as one of the top pharmaceuticals present in the environment. 2,14 MET exposure exhibits adverse effects on aquatic life 15−17 and can accumulate in plants. 18 In addition, its transformation products such as guanylurea (GUA) 19,20 and chlorination byproducts, 21 appear to be toxic and widely distributed.…”

“…The present treatment of WWTPs shows incomplete elimination of MET with removal rates ranging from 41% to more than 98%, and ultimately significant amount of MET from WWTPs is released into the environment . Consequently, the worldwide occurrence of MET has been observed in surface, ground, drinking and coastal waters, sludges, and soils. ,,, It has recently been categorized as one of the top pharmaceuticals present in the environment. , MET exposure exhibits adverse effects on aquatic life − and can accumulate in plants . In addition, its transformation products such as guanylurea (GUA) , and chlorination byproducts, appear to be toxic and widely distributed. ,− …”

Wastewater bacteria remediating the pharmaceutical metformin: Genomes, plasmids and products

“…Metformin has a poor affinity for activated carbon, which is the standard method for removing pharmaceuticals. Additionally, metformin chlorination in WWTPs produces N-chloro species that are toxic to human cells (Armbruster et al, 2015;Liao et al, 2021;Zhang et al, 2021;He et al, 2022). While bioremediation has been considered a viable strategy for dealing with metformin contamination, the extent of pathways and enzymes involved in the drug's microbial metabolism have yet to be elucidated.…”