Environmental risk assessment of metformin and its transformation product guanylurea. I. Environmental fate

Straub, Jürg Oliver; Caldwell, Daniel J.; Davidson, T. Jeffery; D’Aco, Vincent J.; Kappler, Kelly; Robinson, P.; Simon-Hettich, Brigitte; Tell, Joan G.

doi:10.1016/j.chemosphere.2018.10.036

Cited by 46 publications

(25 citation statements)

References 34 publications

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“…These results show that metformin and its intermediate (i.e., biotransformation product guanylurea) are biodegradable with an easily degradable carbon source co-substrate. Nearly complete removal of metformin was observed in the anaerobic section of the reactor, contradicting studies reporting that metformin is only aerobically biodegraded to guanylurea [11,22,24]. A recent study supporting our findings has indicated that complete degradation of guanylurea can also occur in the presence of easily degradable carbon sources [21].…”

Section: Resultscontrasting

confidence: 98%

Treatment of Metformin-Containing Wastewater by a Hybrid Vertical Anaerobic Biofilm-Reactor (HyVAB)

Janka

Carvajal

Wang

et al. 2019

IJERPH

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Several series of batch and continuous experiments were performed to investigate the removal of metformin and other contaminants from two wastewaters: wastewater I (WWI) containing 4 mg/L metformin and wastewater II (WWII) containing 110 g/L butanol. Biomethane potential (BMP) tests on WWII showed 77% of total chemical oxygen demand (tCOD = 110 g/L) degradability, and no apparent inhibition effects were observed. BMP tests on WWI showed an apparent inhibitory effect reflected in lower biogas production with increasing metformin concentration in the wastewater. Continuous flow hybrid vertical anaerobic biofilm (HyVAB®) experiments were consistent with the batch test findings. It was necessary to co-digest WWI (metformin) with WWII (easily degradable organics) to achieve complete metformin removal. After a period of adaptation, WWI and WWII co-digestion achieved up to 98% tCOD removal and 100% metformin removal. Most of the contaminants were removed in the anaerobic section of the HyVAB®, which implies that higher chemical oxygen demand (COD) loads than tested here are possible, given some optimization. The pilot reactor was able to manage organic loads of 11 g COD/d and above 10 mg/L metformin with a removal of 98% and 100% for tCOD and metformin, respectively.

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Section: Resultscontrasting

confidence: 98%

Treatment of Metformin-Containing Wastewater by a Hybrid Vertical Anaerobic Biofilm-Reactor (HyVAB)

Janka

Carvajal

Wang

et al. 2019

IJERPH

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“…The levels of these compounds entering municipal wastewater treatment are likely to increase due to metformin’s broadening pharmacological efficacy, its widespread use, projected increases in the rates of obesity and diabetes, and the emerging new uses for the compound ( 2 , 16 ). There is also evidence that metformin and guanylurea may impact some aquatic species ( 14 , 18 , 19 ). In light of these different impacts, guanylurea is considered in many countries to be one of the most prominent emerging water pollutants ( 20 ).…”

Section: Introductionmentioning

confidence: 99%

Filling in the Gaps in Metformin Biodegradation: a New Enzyme and a Metabolic Pathway for Guanylurea

Tassoulas

Robinson

Martinez‐Vaz

et al. 2021

Appl Environ Microbiol

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The widely prescribed pharmaceutical metformin and its main metabolite guanylurea are currently two of the most common contaminants in surface and wastewater. Guanylurea often accumulates and is poorly, if at all, biodegraded in wastewater treatment plants. This study describes Pseudomonas mendocina strain GU isolated from a municipal wastewater treatment plant using guanylurea as its sole nitrogen source. The genome was sequenced with 36-fold coverage and mined to identify guanylurea degradation genes. The gene encoding the enzyme initiating guanylurea metabolism was expressed, the enzyme purified and characterized. Guanylurea hydrolase, a newly described enzyme, was shown to transform guanylurea to one equivalent of ammonia and guanidine. Guanidine also supports growth as a sole nitrogen source. Cell yields from growth on limiting concentrations of guanylurea revealed that metabolism releases all four nitrogen atoms. Genes encoding complete metabolic transformation were identified bioinformatically, defining the pathway as follows: guanylurea to guanidine to carboxyguanidine to allophanate to ammonia and carbon dioxide. The first enzyme, guanylurea hydrolase, is a member of the isochorismatase-like hydrolase protein family that includes biuret hydrolase and triuret hydrolase. Although homologs, the three enzymes show distinct substrate specificities. Pairwise sequence comparisons and the use of sequence similarity networks allowed fine structure discrimination between the three homologous enzymes and provided insights into the evolutionary origins of guanylurea hydrolase. IMPORTANCE Metformin is a pharmaceutical most prescribed for type 2 diabetes and is now being examined for potential benefits to COVID-19 patients. People taking the drug pass it largely unchanged and it subsequently enters wastewater treatment plants. Metformin has been known to be metabolized to guanylurea. The levels of guanylurea often exceed that of metformin, leading to the former being considered a “dead end” metabolite. Metformin and guanylurea are water pollutants of emerging concern as they persist to reach non-target aquatic life and humans, the latter if it remains in treated water. The present study has identified a Pseudomonas mendocina strain that completely degrades guanylurea. The genome was sequenced and the genes involved in guanylurea metabolism were identified in three widely separated genomic regions. This knowledge advances the idea that guanylurea is not a dead end product and will allow for bioinformatic identification of the relevant genes in wastewater treatment plant microbiomes and other environments subjected to metagenomic sequencing.

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“…To date, there is no data about the concentration of metformin or granylurea in water and wastewater from the São Paulo Metropolitan Region. However, these two compounds may be present in most water bodies and urban reservoirs of the São Paulo Metropolitan Region, taking into account the relationship between prescription levels and concentration in the environment 27 , not to mention the fact that a proportion of untreated sewage flows directly into water bodies and WWTPs do not remove these compounds completely 31 .…”

Section: Discussionmentioning

confidence: 99%

Pharmaceutical market, environmental public policies and water quality: the case of the São Paulo Metropolitan Region, Brazil

et al. 2020

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Water pollution has been an increasing concern for the authorities responsible for planning and executing public policies. In this qualitative research, we have discussed the most sold pharmaceuticals in the São Paulo Metropolitan Region, Brazil, and compared public policies focused on pharmaceuticals and environmental issues among countries/regions. For that, data provided by Close-Up International related to the sales of medicines in the São Paulo Metropolitan Region between April/2016 and April/2017 were collected and processed to identify and quantify the pharmaceutical products. The 300 most sold medicines in the São Paulo Metropolitan Region fall in 26 therapeutic classes, which include 159 drugs. The most sold pharmaceutical products group is nonsteroidal anti-inflammatory drugs (NSAIDs) representing approximately 44.3% of the total. The ten most sold pharmaceuticals sum up 1200 tons. Dipyrone is the first place in mass representing around 488 tons, followed by metformin with around 310 tons commercialized. Public policies focused on pharmaceuticals in the environment still need adjustments to improve reinforcement, even in developed countries. There is no international standard on how to conduct the issue, each country adopting the public policy that best matches to the local. Brazil, despite having some legislation that approaches the theme, still lacks effective public policies and stakeholder awareness. In this aspect, the need for improvement of the reverse logistics system, consumer orientation to the adequate disposal of unused/expired medicines, and the adoption of the unit-dose system as a therapeutic strategy is evident.

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Environmental risk assessment of metformin and its transformation product guanylurea. I. Environmental fate

Cited by 46 publications

References 34 publications

Treatment of Metformin-Containing Wastewater by a Hybrid Vertical Anaerobic Biofilm-Reactor (HyVAB)

Treatment of Metformin-Containing Wastewater by a Hybrid Vertical Anaerobic Biofilm-Reactor (HyVAB)

Filling in the Gaps in Metformin Biodegradation: a New Enzyme and a Metabolic Pathway for Guanylurea

Pharmaceutical market, environmental public policies and water quality: the case of the São Paulo Metropolitan Region, Brazil

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