Publications by authors named "Alexander L N van Nuijs"

85 Publications

Ion Mobility-High-Resolution Mass Spectrometry (IM-HRMS) for the Analysis of Contaminants of Emerging Concern (CECs): Database Compilation and Application to Urine Samples.

Anal Chem 2021 04 12;93(16):6428-6436. Epub 2021 Apr 12.

Toxicological Centre, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.

Ion mobility mass spectrometry (IM-MS)-derived collision cross section (CCS) values can serve as a valuable additional identification parameter within the analysis of compounds of emerging concern (CEC) in human matrices. This study introduces the first comprehensive database of CCS values of 148 CECs and their metabolites including bisphenols, alternative plasticizers (AP), organophosphate flame retardants (OP), perfluoroalkyl chemicals (PFAS), and others. A total of 311 ions were included in the database, whereby the CCS values for 113 compounds are reported for the first time. For 105 compounds, more than one ion is reported. Moreover, the CCS values of several isomeric CECs and their metabolites are reported to allow a distinction between isomers. Comprehensive quality assurance guidelines were implemented in the workflow of acquiring CCS values to ensure reproducible experimental conditions. The reliability and reproducibility of the complied database were investigated by analyzing pooled human urine spiked with 30 AP and OP metabolites at two concentration levels. For all investigated metabolites, the CCS values measured in urine showed a percent error of <1% in comparison to database values. CCS values of OP metabolites showed an average percent error of 0.12% (50 ng/mL in urine) and 0.15% (20 ng/mL in urine). For AP metabolites, these values were 0.10 and 0.09%, respectively. These results show that the provided database can be of great value for enhanced identification of CECs in environmental and human matrices, which can advance future suspect screening studies on CECs.
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http://dx.doi.org/10.1021/acs.analchem.1c00142DOI Listing
April 2021

Changes in drug use in European cities during early COVID-19 lockdowns - A snapshot from wastewater analysis.

Environ Int 2021 Mar 26;153:106540. Epub 2021 Mar 26.

Environmental and Public Health Analytical Chemistry, Research Institute for Pesticides and Water, University Jaume I, Castellón, Spain; Institute for Biodiversity and Ecosystem Dynamics, University of Amsterdam, the Netherlands. Electronic address:

The COVID-19 outbreak has forced countries to introduce severe restrictive measures to contain its spread. In particular, physical distancing and restriction of movement have had important consequences on human behaviour and potentially also on illicit drug use and supply. These changes can be associated with additional risks for users, in particular due to reduced access to prevention and harm reduction activities. Furthermore, there have been limitations in the amount of data about drug use which can be collected due to restrictions. To goal of this study was to obtain information about potential changes in illicit drug use impacted by COVID-19 restrictions. Wastewater samples were collected in seven cities in the Netherlands, Belgium, Spain and Italy at the beginning of lockdowns (March-May 2020). Using previously established and validated methods, levels of amphetamine (AMP), methamphetamine (METH), MDMA, benzoylecgonine (BE, the main metabolite of cocaine) and 11-nor-9-carboxy-Δ-tetrahydrocannabinol (THC-COOH, main metabolite of tetrahydrocannabinol (THC)) were measured and compared with findings from previous years. Important differences in levels of consumed drugs were observed across the considered countries. Whilst for some substances and locations, marked decreases in consumption could be observed (e.g., 50% decrease in MDMA levels compared to previous years). In some cases, similar or even higher levels compared to previous years could be found. Changes in weekly patterns were also observed, however these were not clearly defined for all locations and/or substances. Findings confirm that the current situation is highly heterogeneous and that it remains very difficult to explain and/or predict the effect that the present pandemic has on illicit drug use and availability. However, given the current difficulty in obtaining data due to restrictions, wastewater analysis can provide relevant information about the situation at the local level, which would be hard to obtain otherwise.
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http://dx.doi.org/10.1016/j.envint.2021.106540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997602PMC
March 2021

Application of wastewater-based epidemiology to investigate stimulant drug, alcohol and tobacco use in Lithuanian communities.

Sci Total Environ 2021 Feb 19;777:145914. Epub 2021 Feb 19.

Toxicological Centre, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. Electronic address:

WBE was applied to evaluate illicit drug (i.e. amphetamine, cocaine, MDMA and methamphetamine), alcohol and tobacco use in three Lithuanian cities in 2018 and 2019. Considerable concentrations of methamphetamine and MDMA were found in the three locations, suggesting a specific Lithuanian consumption pattern. Yet, unexpected high concentrations of amphetamine (>4 μg/L) were detected in two samples of Kaunas in 2018. Through the use of chiral analysis and non-target and suspect drug precursor compound screening, these extreme values were confirmed to be the result of direct disposal of amphetamine in the sewers. Furthermore, substantial alcohol use was measured in the three investigated catchment populations of Lithuania with almost 4 standard drinks/day/inhabitant aged 15+ on average in 2019. For tobacco, an average of 5.6 cigarettes/day/inhabitant aged 15+ in 2019 was reported with large discrepancies between WBE figures and sales data, potentially highlighting illegal trade of tobacco products.
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http://dx.doi.org/10.1016/j.scitotenv.2021.145914DOI Listing
February 2021

Electrochemical profiling and liquid chromatography-mass spectrometry characterization of synthetic cathinones: From methodology to detection in forensic samples.

Drug Test Anal 2021 Feb 24. Epub 2021 Feb 24.

AXES Research Group, Department of Bioscience Engineering, University of Antwerp, Antwerp, Belgium.

The emergence of new psychoactive drugs in the market demands rapid and accurate tools for the on-site classification of illegal and legal compounds with similar structures. Herein, a novel method for the classification of synthetic cathinones (SCs) is presented based on their electrochemical profile. First, the electrochemical profile of five common SC (i.e., mephedrone, ethcathinone, methylone, butylone, and 4-chloro-alpha-pyrrolidinovalerophenone) is collected to build calibration curves using square wave voltammetry on graphite screen-printed electrodes (SPEs). Second, the elucidation of the oxidation pathways, obtained by liquid chromatography-high-resolution mass spectrometry, allows the pairing of the oxidation products to the SC electrochemical profile, providing a selective and robust classification. Additionally, the effect of common adulterants and illicit drugs on the electrochemical profile of the SC is explored. Interestingly, a cathodic pretreatment of the SPE allows the selective detection of each SC in presence of electroactive adulterants. Finally, the electrochemical approach is validated with gas chromatography-mass spectrometry by analyzing 26 confiscated samples from seizures and illegal webshops. Overall, the electrochemical method exhibits a successful classification of SC including structural derivatives, a crucial attribute in an ever-diversifying drug market.
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http://dx.doi.org/10.1002/dta.3018DOI Listing
February 2021

Investigation of Biotransformation Products of -Methoxymethylamphetamine and Dihydromephedrone in Wastewater by High-Resolution Mass Spectrometry.

Metabolites 2021 Jan 25;11(2). Epub 2021 Jan 25.

Laboratory of Analytical Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece.

There is a paucity of information on biotransformation and stability of new psychoactive substances (NPS) in wastewater. Moreover, the fate of NPS and their transformation products (TPs) in wastewater treatment plants is not well understood. In this study, batch reactors seeded with activated sludge were set up to evaluate biotic, abiotic, and sorption losses of -methoxymethylamphetamine (PMMA) and dihydromephedrone (DHM) and identify TPs formed during these processes. Detection and identification of all compounds was performed with target and suspect screening approaches using liquid chromatography quadrupole-time-of-flight mass spectrometry. Influent and effluent 24 h composite wastewater samples were collected from Athens from 2014 to 2020. High elimination rates were found for PMMA (80%) and DHM (97%) after a seven-day experiment and degradation appeared to be related to biological activity in the active bioreactor. Ten TPs were identified and the main reactions were - and -demethylation, oxidation, and hydroxylation. Some TPs were reported for the first time and some were confirmed by reference standards. Identification of some TPs was enhanced by the use of an in-house retention time prediction model. Mephedrone and some of its previously reported human metabolites were formed from DHM incubation. Retrospective analysis showed that PMMA was the most frequently detected compound.
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http://dx.doi.org/10.3390/metabo11020066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912097PMC
January 2021

Stability of phosphatidylethanol 16:0/18:1 in authentic and spiked whole blood.

Drug Test Anal 2021 Jan 4. Epub 2021 Jan 4.

Toxicological Centre, University of Antwerp, Antwerp, Belgium.

Phosphatidylethanol 16:0/18:1 (PEth) is the most abundant homologue of the phosphatidylethanol group of phospholipids. Formed only in the presence of ethanol, PEth is used as a biomarker in whole blood to provide information about the consumption of alcohol. As information on the storage life of PEth is essential for its beneficial use as a biomarker, this study investigated the stability of PEth in spiked and authentic whole blood samples stored at 4°C. Human whole blood samples (n = 23) and spiked whole blood samples (n = 7) with a concentration range between 5 and 2000 ng/ml were analysed at specific time intervals, up to 90 days. Differences were evident between the stability of authentic and spiked samples. PEth was stable at 4°C for 60 days (concentrations within 15% of initial concentration) in authentic samples, whereas spiked samples were stable for up to 30 days. This study emphasizes the importance of including authentic samples in stability experiments.
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http://dx.doi.org/10.1002/dta.2995DOI Listing
January 2021

Electrochemistry of Intact Versus Degraded Cephalosporin Antibiotics Facilitated by LC-MS Analysis.

Anal Chem 2021 02 4;93(4):2394-2402. Epub 2021 Jan 4.

AXES Research Group, Groenenborgerlaan 171, 2020 Antwerp, Belgium.

The electrochemical detection of cephalosporins is a promising approach for the monitoring of cephalosporin levels in process waters. However, this class of antibiotics, like penicillins, is composed of chemically active molecules and susceptible to hydrolysis and aminolysis of the four membered β-lactam ring present. In order to develop a smart monitoring strategy for cephalosporins, the influence of degradation (hydrolysis and aminolysis) on the electrochemical fingerprint has to be taken into account. Therefore, an investigation was carried out to understand the changes of the voltammetric fingerprints upon acidic and alkaline degradation. Changes in fingerprints were correlated to the degradation pathways through the combination of square wave voltammetry and liquid chromatography quadrupole time-of-flight analysis. The characteristic electrochemical signals of the β-lactam ring disappeared upon hydrolysis. Additional oxidation signals that appeared after degradation were elucidated and linked to different degradation products, and therefore, enrich the voltammetric fingerprints with information of the state of the cephalosporins. The applicability of the electrochemical monitoring system was explored by the analysis of the intact and degraded industrial process waters containing the key intermediate 7-aminodeacetoxycephalosporanic acid (7-ADCA). Clearly, the intact process samples exhibited the expected core signals of 7-ADCA and could be quantified, while the degraded samples only showed the newly formed degradation products.
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http://dx.doi.org/10.1021/acs.analchem.0c04286DOI Listing
February 2021

An exploratory approach for an oriented development of an untargeted hydrophilic interaction liquid chromatography-mass spectrometry platform for polar metabolites in biological matrices.

J Chromatogr A 2021 Jan 15;1637:461807. Epub 2020 Dec 15.

Toxicological Centre, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. Electronic address:

The analysis of polar metabolites based on liquid chromatography-mass spectrometry (LC-MS) methods should take into consideration the complexity of interactions in LC columns to be able to cover a broad range of metabolites of key biological pathways. Therefore, in this study, different chromatographic columns were tested for polar metabolites including reversed-phase and hydrophilic interaction liquid chromatography (HILIC) columns. Based on a column screening, two new generations of zwitterionic HILIC columns were selected for further evaluation. A tree-based method optimization was applied to investigate the chromatographic factors affecting the retention mechanisms of polar metabolites with zwitterionic stationary phases. The results were evaluated based on a scoring system which was applied for more than 80 polar metabolites with a high coverage of key human metabolic pathways. The final optimized methods showed high complementarity to analyze a wide range of metabolic classes including amino acids, small peptides, sugars, amino sugars, phosphorylated sugars, organic acids, nucleobases, nucleosides, nucleotides and acylcarnitines. Optimized methods were applied to analyze different biological matrices, including human urine, plasma and liver cell extracts using an untargeted approach. The number of high-quality features (< 30% median relative standard deviation) ranged from 3,755 for urine to 5,402 for the intracellular metabolome of liver cells, showing the potential of the methods for untargeted purposes.
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http://dx.doi.org/10.1016/j.chroma.2020.461807DOI Listing
January 2021

Demonstrating the involvement of an active efflux mechanism in the intestinal absorption of chlorogenic acid and quinic acid using a Caco-2 bidirectional permeability assay.

Food Funct 2021 Jan 18;12(1):417-425. Epub 2020 Dec 18.

Natural Products and Food - Research & Analysis (NatuRA), University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.

Scope: Chlorogenic acid (5-caffeoylquinic acid), the most prominent polyphenolic compound in coffee, has been attributed multiple health-promoting effects such as anti-inflammatory, antidiabetic and antioxidative effects. These effects are dependent on the bioavailability of chlorogenic acid, which is determined by the pharmacokinetic properties: absorption, distribution, metabolism and excretion (ADME). In order to have a better understanding of the biological properties of chlorogenic acid and to optimize formulation and dosing of chlorogenic acid-containing food supplements, information on the absorption of chlorogenic acid and its microbial biotransformation products is of essence.

Methods And Results: In the present work, the intestinal absorption of chlorogenic acid and quinic acid, one of its most prominent intestinal biotransformation products, was studied by an in vitro permeability assay using a human Caco-2 cell line model. For both chlorogenic acid and quinic acid, the involvement of an active efflux mechanism was demonstrated, suggesting an overall low intestinal absorption.

Conclusions: An overall low intestinal absorption for chlorogenic acid and quinic acid was reported given the involvement of an active efflux mechanism. These findings could aid in the development of optimal formulation and dosing strategies of chlorogenic acid in food supplements in order to obtain beneficial health effects.
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http://dx.doi.org/10.1039/d0fo02629hDOI Listing
January 2021

Identifying Electrochemical Fingerprints of Ketamine with Voltammetry and Liquid Chromatography-Mass Spectrometry for Its Detection in Seized Samples.

Anal Chem 2020 10 18;92(19):13485-13492. Epub 2020 Sep 18.

AXES Group, Bioscience Engineering Department, University of Antwerp, Groenenborgerlaan 171, 2020 Antwerp, Belgium.

Herein, a straightforward electrochemical approach for the determination of ketamine in street samples and seizures is presented by employing screen-printed electrodes (SPE). Square wave voltammetry (SWV) is used to study the electrochemical behavior of the illicit drug, thus profiling the different oxidation states of the substance at different pHs. Besides, the oxidation pathway of ketamine on SPE is investigated for the first time with liquid chromatography-high-resolution mass spectrometry. Under the optimized conditions, the calibration curve of ketamine at buffer solution (pH 12) exhibits a sensitivity of 8.2 μA μM, a linear relationship between 50 and 2500 μM with excellent reproducibility (RSD = 2.2%, at 500 μM, = 7), and a limit of detection (LOD) of 11.7 μM. Subsequently, binary mixtures of ketamine with adulterants and illicit drugs are analyzed with SWV to investigate the electrochemical fingerprint. Moreover, the profile overlapping between different substances is addressed by the introduction of an electrode pretreatment and the integration of a tailor-made script for data treatment. Finally, the approach is tested on street samples from forensic seizures. Overall, this system allows for the on-site identification of ketamine by law enforcement agents in an easy-to-use and rapid manner on cargos and seizures, thereby disrupting the distribution channel and avoiding the illicit drug reaching the end-user.
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http://dx.doi.org/10.1021/acs.analchem.0c02810DOI Listing
October 2020

Quantification of 54 Benzodiazepines and Z-Drugs, Including 20 Designer Ones, in Plasma.

J Anal Toxicol 2021 Feb;45(2):141-153

Toxicological Centre, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.

Benzodiazepines are widely used in the treatment of sleep and anxiety disorders, as well as epileptic seizures and alcohol withdrawal because of their broad therapeutic index and low cost. Due to their central nervous system depressant effects they are also often implicated in traffic accidents and drug-related intoxications. With an increasing number of designer benzodiazepines used in a recreational setting, there is a need for analytical methods to be able to quantify both the prescribed and designer benzodiazepines. A liquid chromatography-triple quadrupole mass spectrometry method was developed for the quantification of 34 prescribed and 20 designer benzodiazepines in plasma. Different sample preparation strategies, including protein precipitation, liquid-liquid extraction, solid-phase extraction and mini-QuEChERS, were tested. The best recoveries for all compounds of interest were obtained with a liquid-liquid extraction using methyl-tertiary-butyl-ether and 500 μL plasma. The method was fully validated according to the European Medicines Agency guidelines for all compounds, except pivoxazepam, which is included for qualitative purposes only. In-sample stability issues were observed for cloxazolam, both at ambient temperature and during long-term storage at -20°C. Due to the large number of compounds included, the simple and time-efficient sample preparation and the relatively inexpensive instrumentation used, the presented method can be readily implemented in both therapeutic drug monitoring and forensic analyses.
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http://dx.doi.org/10.1093/jat/bkaa059DOI Listing
February 2021

Unraveling the Mechanisms Behind the Complete Suppression of Cocaine Electrochemical Signals by Chlorpromazine, Promethazine, Procaine, and Dextromethorphan.

Anal Chem 2019 12 27;91(24):15453-15460. Epub 2019 Nov 27.

AXES Research Group , University of Antwerp , Groenenborgerlaan 171 , 2020 Antwerp , Belgium.

The present work investigates the challenges accompanied by the electrochemical cocaine detection in physiological conditions (pH 7) in the presence of chlorpromazine, promethazine, procaine, and dextromethorphan, frequently used cutting agents in cocaine street samples. The problem translates into the absence of the cocaine oxidation signal (signal suppression) when in a mixture with one of these compounds, leading to false negative results. Although a solution to this problem was provided through earlier experiments of our group, the mechanisms behind the suppression are now fundamentally investigated via electrochemical and liquid chromatography quadrupole-time-of-flight mass spectrometry (LC-QTOF-MS) strategies. The latter was used to confirm the passivation of the electrodes due to their interaction with promethazine and chlorpromazine. Electron transfer mechanisms were further identified via linear sweep voltammetry. Next, adsorption experiments were performed on the graphite screen printed electrodes both with and without potential assistance in order to confirm if the suppression of the cocaine signals is due to passivation induced by the cutting agents or their oxidized products. The proposed strategies allowed us to identify the mechanisms of cocaine suppression for each cutting agent mentioned. Suppression due to procaine and dextromethorphan is caused by fouling of the electrode surface by their oxidized forms, while for chlorpromazine and promethazine the suppression of the cocaine signal is related to the strong adsorption of these (nonoxidized) cutting agents onto the graphite electrode surface. These findings provide fundamental insights in possible suppression and other interfering mechanisms using electrochemistry in general not only in the drug detection sector.
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http://dx.doi.org/10.1021/acs.analchem.9b03128DOI Listing
December 2019

Spatio-temporal assessment of illicit drug use at large scale: evidence from 7 years of international wastewater monitoring.

Addiction 2020 01 23;115(1):109-120. Epub 2019 Oct 23.

Faculty of Fisheries and Protection of Waters, University of South Bohemia in Ceske Budejovice, Zatisi, Czech Republic.

Background And Aims: Wastewater-based epidemiology is an additional indicator of drug use that is gaining reliability to complement the current established panel of indicators. The aims of this study were to: (i) assess spatial and temporal trends of population-normalized mass loads of benzoylecgonine, amphetamine, methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) in raw wastewater over 7 years (2011-17); (ii) address overall drug use by estimating the average number of combined doses consumed per day in each city; and (iii) compare these with existing prevalence and seizure data.

Design: Analysis of daily raw wastewater composite samples collected over 1 week per year from 2011 to 2017.

Setting And Participants: Catchment areas of 143 wastewater treatment plants in 120 cities in 37 countries.

Measurements: Parent substances (amphetamine, methamphetamine and MDMA) and the metabolites of cocaine (benzoylecgonine) and of Δ -tetrahydrocannabinol (11-nor-9-carboxy-Δ -tetrahydrocannabinol) were measured in wastewater using liquid chromatography-tandem mass spectrometry. Daily mass loads (mg/day) were normalized to catchment population (mg/1000 people/day) and converted to the number of combined doses consumed per day. Spatial differences were assessed world-wide, and temporal trends were discerned at European level by comparing 2011-13 drug loads versus 2014-17 loads.

Findings: Benzoylecgonine was the stimulant metabolite detected at higher loads in southern and western Europe, and amphetamine, MDMA and methamphetamine in East and North-Central Europe. In other continents, methamphetamine showed the highest levels in the United States and Australia and benzoylecgonine in South America. During the reporting period, benzoylecgonine loads increased in general across Europe, amphetamine and methamphetamine levels fluctuated and MDMA underwent an intermittent upsurge.

Conclusions: The analysis of wastewater to quantify drug loads provides near real-time drug use estimates that globally correspond to prevalence and seizure data.
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http://dx.doi.org/10.1111/add.14767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973045PMC
January 2020

Optimization of an in vitro gut microbiome biotransformation platform with chlorogenic acid as model compound: From fecal sample to biotransformation product identification.

J Pharm Biomed Anal 2019 Oct 10;175:112768. Epub 2019 Jul 10.

Natural Products and Food - Research & Analysis (NatuRA), University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. Electronic address:

Recent data clearly show that the gut microbiota plays a significant role in the biotransformation of many endogenous molecules and xenobiotics, leading to a potential influence of this microbiotic metabolism on activation, inactivation and possible toxicity of these compounds. To study the colonic biotransformation of xenobiotics by the gut microbiome, in vitro models are often used as they allow dynamic and multiple sampling overtime. However, the pre-analytical phase should be carefully optimized to enable biotransformation product identification representative for the in vivo situation. During this study, chlorogenic acid was used as a model compound to optimize a ready-to-use gut microbiome biotransformation platform using an in vitro gastrointestinal dialysis-model with colon phase together with an instrumental platform using liquid chromatography coupled to high resolution mass spectrometry (LC-QTOF-MS). Identification of the biotransformation products of chlorogenic acid was performed using complementary suspect and non-targeted data analysis approaches (MZmine + R and MPP workflow). Concerning the pre-analytical phase, (i) the influence of different incubation media (Wilkins-Chalgren Anaerobic Broth (WCB) and (versus) phosphate buffer) and different incubation times (prior to implementation in the colonic stage of the dialysis model) on fecal bacterial composition and concentration were investigated and (ii) four different sample preparation methods (centrifugation, extraction, sonication and freeze-drying) were evaluated targeting colonic biotransformation of chlorogenic acid. WCB as incubation medium showed to introduce substantial variation in the bacterial composition of the fecal samples, while the sterile phosphate buffer guaranteed a closer resemblance to the in vivo composition. Furthermore, incubation during 24 h in sterile phosphate buffer as medium showed no significant increase or decrease in anaerobic bacterial concentration, concluding that incubation prior to the colonic stage is not needed. Concerning sample preparation, centrifugation, sonication and extraction gave similar results, while freeze-drying appeared to be inferior. The extraction method was selected as an optimal sample preparation method given the quick execution together with a good instrumental sensitivity. This study optimized a ready-to-use platform to investigate colonic biotransformation of xenobiotics by using chlorogenic acid as a model compound. This platform can be used in the future to study differences in colonic biotransformation of xenobiotics using fecal samples of different patient groups.
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http://dx.doi.org/10.1016/j.jpba.2019.07.016DOI Listing
October 2019

Suspect and Nontargeted Strategies to Investigate Human Biotransformation Products of Emerging Environmental Contaminants: The Benzotriazoles.

Environ Sci Technol 2019 Sep 6;53(17):10462-10469. Epub 2019 Jul 6.

Toxicological Center , University of Antwerp , Universiteitsplein 1 , Wilrijk, 2610 Antwerp , Belgium.

Benzotriazole derivatives (BTRs) are high production volume chemicals involved in a wide range of applications and consumer products resulting in their ubiquitous presence in environmental matrices. Yet, the human exposure assessment to these chemicals is limited since it is based only on the analysis of parent compounds in biological matrices. The objective of this study was to investigate the human biotransformation for three widely used BTRs and to stepwise examine the role of Phase I and II enzymes (cytochrome P450 (CYP), uridine glucuronic acid transferase (UGT), and sulfotransferase (SULT)) in their biotransformation. Extracts with generated biotransformation products (bioTPs) were analyzed using liquid chromatography coupled to quadrupole-time-of-flight mass spectrometry (LC-QTOF-MS), followed by their identification based on a workflow combining suspect and nontargeted strategies. Ten bioTPs were identified for 1-benzotriazole, 14 for tolyltriazole, and 14 for 5-chloro-1-benzotriazole. Most of the proposed bioTPs were identified and structurally elucidated for the first time. Based on these findings, possible bioTPs and metabolic transformation pathways were subsequently predicted for other structurally close BTR derivatives. Our findings provide new identified biotransformation products for future biomonitoring studies and emphasize that it is important to investigate the biotransformation pathway to assess overall exposure to xenobiotics.
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http://dx.doi.org/10.1021/acs.est.9b02429DOI Listing
September 2019

Development and validation of an analytical procedure to detect spatio-temporal differences in antidepressant use through a wastewater-based approach.

Talanta 2019 Aug 15;200:340-349. Epub 2019 Mar 15.

Toxicological Centre, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. Electronic address:

Wastewater-based epidemiology applies the analysis of human metabolic excretion products of xenobiotics in wastewater to estimate the community-wide use of these compounds. A new bioanalytical method was developed, optimised and validated for the analysis of a broad range of antidepressants and their metabolites at trace concentrations in influent wastewater. The assay was based on solid-phase extraction and liquid chromatography coupled to tandem mass spectrometry. For most compounds, Oasis® HLB cartridges were used for sample preparation. Oasis® MCX cartridges were used for extraction of normirtazapine, moclobemide, sertraline, and melitracen in particular. The Kinetex XBC18 column with a gradient elution resulted in appropriate separation for the analytes under investigation. Validation was done according to the European Medicines Agency guidelines on bioanalytical method validation. For 27 compounds, the performance criteria met the requirements for method validation. For these analytes, the lower limit of quantification (LLOQ) ranged between 1 and 25 ng/L. Furthermore, all targeted biomarkers showed high in-sample stability during 24 h, with the exception of mianserin. The validated assay was applied to influent wastewater samples collected from four wastewater treatment plants in Belgium. Among these four locations, a total of 18 out of 27 biomarkers for antidepressant use were present in the samples in concentrations above the LLOQ. Additionally, the proposed methodology proved capable of analysing high resolution spatio-temporal trends. Mann-Kendall trend analyses showed that antidepressant use is stable throughout the week, except for trazodone which increased throughout the week.
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http://dx.doi.org/10.1016/j.talanta.2019.03.052DOI Listing
August 2019

Development and validation of a bioanalytical assay based on liquid chromatography-tandem mass spectrometry for measuring biomarkers of exposure of alternative plasticizers in human urine and serum.

Talanta 2019 Jun 5;198:230-236. Epub 2019 Feb 5.

Toxicological Centre, Department of Pharmaceutical Sciences, University of Antwerp, 2610 Wilrijk, Belgium. Electronic address:

Alternative plasticizers (APs) have been increasingly used in the last decade to replace conventional phthalate esters, in particular di(2-ethylhexyl) phthalate (DEHP), due to the toxicity of the latter. However, there is currently very little data about the toxicity of and exposure to APs. No method exists so far for the analysis of multiple exposure biomarkers. The objective of this work consisted in developing a simple bioanalytical procedure for the analysis of multiple exposure biomarkers of APs in human urine and serum. Focus was set on metabolites of di(2-propylheptyl) phthalate (DPrHpP), di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH), di(2-ethylhexyl) terephthalate (DEHTP) and di-2-ethylhexyl adipate (DEHA). A sample preparation protocol was developed and optimized using Oasis HLB solid-phase extraction (SPE) cartridges. Subsequently, an instrumental method based on liquid-chromatography coupled to tandem mass spectrometry (LC-MS/MS) was optimized. Following established guidelines, the sample preparation and instrumental methods were validated in terms of recovery, matrix effects, carry-over, linearity, limits of quantification, within- and between-run precision and trueness. Obtained results were satisfactory for all compounds except for one of the metabolites of DEHA (i.e., mono(2-ethylhexyl) adipate (MEHA)). A pilot biomonitoring study was carried out to assess the method's ability to detect and quantify target analytes in human urine and serum. In urine, most analytes could be detected with frequencies ranging from 8% for mono(2-ethyl-5-hydroxyhexyl) adipate (OH-MEHA) and cyclohexane-1,2-dicarboxylic mono hydroxyisononyl ester (OH-MINCH) to 92% for mono(2-ethyl-5-oxohexyl) adipate (oxo-MEHA), whilst most compounds could not be detected in serum, except for mono(2-ethylhexyl) terephthalate (MEHTP) and mono-(2-propyl-6-hydroxyheptyl) phthalate (OH-MPrHpP) which were detected in all samples. The obtained results show that the developed method can be used to simultaneously analyse multiple exposure biomarkers to APs in human urine and serum.
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http://dx.doi.org/10.1016/j.talanta.2019.02.024DOI Listing
June 2019

Cephalosporin Antibiotics: Electrochemical Fingerprints and Core Structure Reactions Investigated by LC-MS/MS.

Anal Chem 2019 02 15;91(3):2035-2041. Epub 2019 Jan 15.

Chemistry Department , AXES Research Group , Groenenborgerlaan 171 , 2020 Antwerp , Belgium.

Electrochemistry and exploiting electrochemical fingerprints is a potent approach to address newly emerging surveillance needs, for instance, for antibiotics. However, a comprehensive insight into the electrochemical oxidation behavior and mechanism is required for this sensing strategy. To address the lack of knowledge of the voltammetric behavior of the cephalosporin antibiotics, a selection of cephalosporin antibiotics and two main intermediates were subjected to an electrochemical study of their redox behavior by means of pulsed voltammetric techniques and small-scale electrolysis combined with HPLC-MS/MS analyses. Surprisingly, the detected oxidation products did not fit the earlier suggested oxidation of the sulfur group to the corresponding sulfoxide. The influence of different side chains, both at the three and seven position of the β-lactam core structure on the electrochemical fingerprint, were investigated. Additional oxidation signals at lower potentials were elucidated and linked to different side chains. These signals were further exploited to allow simultaneous detection of different cephalosporins in one voltammetric sweep. These fundamental insights can become the building blocks for a new on-site screening method.
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http://dx.doi.org/10.1021/acs.analchem.8b04487DOI Listing
February 2019

Advancing the Zebrafish embryo test for endocrine disruptor screening using micro-injection: Ethinyl estradiol as a case study.

Environ Toxicol Chem 2019 03 11;38(3):533-547. Epub 2019 Feb 11.

Zebrafishlab, Veterinary Physiology and Biochemistry, Department of Veterinary Sciences, University of Antwerp, Wilrijk, Belgium.

Fish (embryo) toxicity test guidelines are mostly based on aquatic exposures. However, in some cases, other exposure routes can be more practical and relevant. Micro-injection into the yolk of fish embryos could offer a particular advantage for administering hydrophobic compounds, such as many endocrine disruptors. Single-dose micro-injection was compared with continuous aquatic exposure in terms of compound accumulation and biological responses. 17α-Ethinyl estradiol (EE2) was used as a model compound. First, the optimal solvent and droplet size were optimized, and needle variation was assessed. Next, biological endpoints were evaluated. The accumulated internal dose of EE2 decreased over time in both exposure scenarios. Estrogen receptor activation was concentration/injected dose dependent, increased daily, and was related to esr2b transcription. Transcription of vitellogenin 1 (vtg1) and brain aromatase (cyp19a1b) was induced in both scenarios, but the cyp19a1b transcription pattern differed between routes. Injection caused an increase in cyp19a1b transcripts from 48 hours post fertilization (hpf) onward, whereas after aquatic exposure the main increase occurred between 96 and 120 hpf. Some malformations only occurred after injection, whereas others were present for both scenarios. We conclude that responses can differ between exposure routes and therefore micro-injection is not a direct substitute for, but can be complementary to aquatic exposure. Nevertheless, vtg1and cyp19a1b transcription and estrogen receptor activation are suitable biomarkers for endocrine disruptor screening in both scenarios. Environ Toxicol Chem 2019;38:533-547. © 2018 SETAC.
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http://dx.doi.org/10.1002/etc.4343DOI Listing
March 2019

Suspect and non-target screening workflows to investigate the in vitro and in vivo metabolism of the synthetic cannabinoid 5Cl-THJ-018.

Drug Test Anal 2019 Mar 23;11(3):479-491. Epub 2018 Oct 23.

Toxicological Centre, University of Antwerp, Antwerp, Belgium.

The use of synthetic cannabinoids causes similar effects as Δ -tetrahydrocannabinol and long-term (ab)use can lead to health hazards and fatal intoxications. As most investigated synthetic cannabinoids undergo extensive biotransformation, almost no parent compound can be detected in urine, which hampers forensic investigations. Limited information about the biotransformation products of new synthetic cannabinoids makes the detection of these drugs in various biological matrices challenging. This study aimed to identify the main in vitro biotransformation pathways of 5Cl-THJ-018 and to compare these findings with an authentic urine sample of a 5Cl-THJ-018 user. The synthetic cannabinoid was incubated with pooled human liver microsomes and cytosol to simulate phase I and phase II biotransformations. Resulting extracts were analyzed with liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). Three different data analysis workflows were applied to identify biotransformation products. A suspect screening workflow used an in-house database built from literature data and in silico biotransformation predictions. Two non-target screening workflows used a commercially available software and an open-source software for mass spectrometry data processing. A total of 23 in vitro biotransformation products were identified, with hydroxylation, oxidative dechlorination, and dihydrodiol formation pathways as the main phase I reactions. Additionally, five glucuronidated and three sulfated phase II conjugates were identified. The predominant in vivo pathway was through oxidative dechlorination and in total six metabolites of 5Cl-THJ-018 were identified. Biotransformation products both in vitro and in vivo were successfully identified using complementary suspect and non-target screening workflows.
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http://dx.doi.org/10.1002/dta.2508DOI Listing
March 2019

Levels of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in raw wastewater as an innovative perspective for investigating population-wide exposure to third-hand smoke.

Sci Rep 2018 09 5;8(1):13254. Epub 2018 Sep 5.

Toxicological Centre, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.

Tobacco smoking is the major cause of many chronic diseases, especially lung cancer. Knowledge about population-wide tobacco use and exposure is essential to characterise its burden on public health and evaluate policy efficacy. Obtaining such knowledge remains challenging with current methods (e.g., surveys, biomonitoring) but can be achievable with wastewater analysis, a promising tool of retrieving epidemiology information. This study examined population-wide exposure to tobacco toxicants and carcinogens through wastewater analysis and explored relationships among these chemicals. Cotinine, trans-3'-hydroxycotinine, anabasine, anatabine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were analysed in samples from Greece, Switzerland and Belgium, where tobacco control policies are different. Measured per-capita mass loads were ranked as: nicotine biomarkers ≫ tobacco markers > carcinogens. Relationships between nicotine biomarkers and tobacco markers implied substantial use of non-tobacco nicotine items besides tobacco products. Geographic profiles of tobacco markers revealed higher levels in Geneva and Athens than Geraardsbergen and Ninove. Environmental third-hand smoke led to NNK detection, with elevated levels observed in Athens where indoor smoking is widespread, posing potential health risks to the population. Our novel outcomes are relevant for public health authorities as they provide indications about external exposure and can thus be used to plan and evaluate tobacco control policies.
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http://dx.doi.org/10.1038/s41598-018-31324-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125383PMC
September 2018

Validation of a simple, fast liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of 40 antidepressant drugs or their metabolites in plasma.

Clin Chim Acta 2018 Oct 13;485:243-257. Epub 2018 Jul 13.

Toxicological Centre, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium. Electronic address:

Introduction: Antidepressant (AD) use has increased significantly over the last decades. Therapeutic drug monitoring is recommended for compliance, toxicity and treatment efficiency. ADs also show a high prevalence in forensic cases. Few methods have been developed that combine a fast, easy sample clean-up with a quantification based on liquid chromatography-triple quadrupole mass spectrometry (LC-QQQ).

Methodology: A liquid-liquid extraction (LLE) was performed using 200 μL of plasma. The evaporated and reconstituted upper fraction was injected on a LC-QQQ system monitoring 3 transitions per compound. The method was fully validated according to international guidelines.

Results & Discussion: The chromatographic run time was under 12 min. The LLE was successful in removing interferences with minimal sensitivity loss. Calibration curves ranged from sub-therapeutic to toxic concentrations. Quality control samples showed high accuracy (81%-119%) and precision (≤14%) within and between batches. Stability was tested at ambient temperature and -20 °C. The method was successfully applied to external quality control and case samples.

Conclusion: The presented method successfully quantifies 40 compounds of interest. Because of a simple sample clean-up, a relatively short chromatographic run and a wide calibration range this method can be implemented in therapeutic drug monitoring, forensic research and related fields.
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http://dx.doi.org/10.1016/j.cca.2018.06.047DOI Listing
October 2018

Assessment of ethyl sulphate in hair as a marker for alcohol consumption using liquid chromatography-tandem mass spectrometry.

Drug Test Anal 2018 Oct 19;10(10):1566-1572. Epub 2018 Jun 19.

Toxicological Centre, University of Antwerp, Belgium.

Ethyl glucuronide (EtG) and ethyl sulphate (EtS) are 2 non-oxidative and direct metabolites of ethanol. EtG is known to accumulate in hair and has proved to be a reliable biomarker for detection of chronic alcohol consumption. EtS has been analysed in blood and urine but has never been reported in hair. This article presents the first analytical assay based on liquid chromatography coupled to tandem mass spectrometry for the quantification of EtS in hair. Sample preparation, chromatographic, and mass spectrometric parameters, such as solid-phase extraction, column type, and transitions were optimised. The method was validated according to the guidelines of the European Medicine Agency, fulfilling the requirements for limit of quantification (LOQ), linearity, accuracy, precision, carry-over, matrix effects, and recovery. Linearity ranged from 5 to 500 pg mg and the LOQ was achieved at 5 pg mg . The novel method was successfully applied to hair samples (n = 40) from patients treated for alcohol use disorders. EtS concentrations in hair ranged from 24 to 1776 pg mg , while EtG concentrations in hair ranged from 1 to 1149 pg mg . Hair concentrations of EtS and EtG were compared to assess the relationship between both biomarkers. There was a significant and positive correlation between EtS and EtG in hair, suggesting that EtS can be used as a biomarker for alcohol consumption. Relatively high basal EtS levels were observed in alcohol-abstinent persons, comparable to what has been reported for EtG. The developed analytical procedure offers an alternative method to prove alcohol consumption using hair analysis.
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http://dx.doi.org/10.1002/dta.2410DOI Listing
October 2018

Wastewater Analysis for Community-Wide Drugs Use Assessment.

Handb Exp Pharmacol 2018;252:543-566

Department of Chemistry, University of Bath, Bath, UK.

Wastewater-based epidemiology (WBE) complements existing epidemiology-based estimation techniques and provides objective, evidence-based estimates of illicit drug use. After consumption, biomarkers - drugs and their metabolites - excreted to toilets and flushed into urban sewer networks can be measured in raw wastewater samples. The quantified loads can serve as an estimate for the collective consumption of all people contributing to the wastewater sample. This transdisciplinary approach, further explained in this chapter, has developed, matured and is now established for monitoring substances such as cocaine and amphetamine-type stimulants. Research currently underway is refining WBE to new applications including new psychoactive substances (NPS).
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http://dx.doi.org/10.1007/164_2018_111DOI Listing
June 2019

Analysis of N,N-dimethylamphetamine in wastewater - a pyrolysis marker and synthesis impurity of methamphetamine.

Drug Test Anal 2018 Oct 20;10(10):1590-1598. Epub 2018 Jul 20.

Queensland Alliance for Environmental Health Sciences, The University of Queensland, Coopers Plains, Australia.

The increased availability of high purity crystalline methamphetamine (MA) in Australia raised concerns because of high dosages and its potential consumption through inhalation. The present work investigates the possibility of using wastewater levels of N,N-dimethylamphetamine (DMA), a pyrolysis by-product, as an indirect indicator of MA smoking. A dedicated liquid chromatography quadrupole-time-of-flight mass spectrometry (LC-QToF-MS) method was set up to detect and quantify DMA in wastewater samples. Wastewater samples were collected from 8 locations across Australia during the period 2011-2016. Data about the abundance of DMA in MA seizures as well as in residues from drug paraphernalia were obtained from forensic laboratories in Australia. DMA/MA ratios measured in wastewater ranged from 0.0001 to 0.09 (median 0.007). DMA/MA ratios in bulk seizures are generally below 0.0025, with a median value of 0.0004, whilst residues in paraphernalia ranged from 0.031 to 3.37. DMA/MA ratios in wastewater decreased between 2011 and 2016, in parallel to an increase in MA loads. Furthermore, wastewater analyses highlighted a strong positive correlation between DMA/MA ratios and per capita MA use (Pearson's correlation ρ= 0.61, p-value <0.001). Nonetheless, geographical specificities could be highlighted between the investigated locations. The obtained data could help authorities detect hot spots of drug use as well as to plan specific intervention campaigns to tackle the issue. In future, simultaneous analysis of DMA and MA in both wastewater and seizures could improve our understanding about MA use and its consumption patterns.
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http://dx.doi.org/10.1002/dta.2419DOI Listing
October 2018

Mining the Chemical Information on Urban Wastewater: Monitoring Human Exposure to Phosphorus Flame Retardants and Plasticizers.

Environ Sci Technol 2018 06 11;52(12):6996-7005. Epub 2018 Jun 11.

Toxicological Centre , University of Antwerp , Universiteitsplein 1 , 2610 Wilrijk , Belgium.

At the individual level, exposure to contaminants is generally assessed through the analysis of specific biomarkers in biological matrices. However, these studies are costly and logistically demanding, limiting their applicability to monitor population-wide exposure over time and space. By focusing on a selection of exposure biomarkers to phosphorus flame retardants and plasticizers (PFRs), this study aims to explore the possibility of using wastewater as a complementary source of information about exposure. Wastewater samples were collected from five cities in Europe and analyzed using a previously established method. Substantial differences in biomarker levels were observed between the investigated catchments, suggesting differences in exposure. Time trends in biomarkers observed between 2013 and 2016 were found to agree with results from human biomonitoring studies and reports about production volumes. Using Monte Carlo simulations, average urinary concentrations were estimated. These were generally higher compared to results from human biomonitoring studies. Various explanations for these differences were formulated (i.e., other excretion routes, external sources and different sampling approaches). Obtained results show that wastewater analysis provides unique information about geographical and temporal differences in exposure, which would be difficult to gather using other monitoring tools.
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http://dx.doi.org/10.1021/acs.est.8b01279DOI Listing
June 2018

Investigating in-sewer transformation products formed from synthetic cathinones and phenethylamines using liquid chromatography coupled to quadrupole time-of-flight mass spectrometry.

Sci Total Environ 2018 Sep 6;634:331-340. Epub 2018 Apr 6.

Toxicological Center, Department of Pharmaceutical Sciences, Campus Drie Eiken, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.

Recent studies have demonstrated the role of biofilms on the stability of drug residues in wastewater. These factors are pertinent in wastewater-based epidemiology (WBE) when estimating community-level drug use. However, there is scarce information on the biotransformation of drug residues in the presence of biofilms and the potential use of transformation products (TPs) as biomarkers in WBE. The purpose of this work was to investigate the formation of TPs in sewage reactors in the presence of biofilm mimicking conditions during in-sewer transport. Synthetic cathinones (methylenedioxypyrovalerone, methylone, mephedrone) and phenethylamines (4-methoxy-methamphetamine and 4-methoxyamphetamine) were incubated in individual reactors over a 24h period. Analysis of parent species and TPs was carried out using liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (LC-QToFMS). Identification of TPs was done using suspect and non-target workflows. In total, 18 TPs were detected and identified with reduction of β-keto group, demethylenation, demethylation, and hydroxylation reactions observed for the synthetic cathinones. For the phenethylamines, N- and O-demethylation reactions were identified. Overall, the experiments showed varying stability for the parent species in wastewater in the presence of biofilms. The newly identified isomeric forms of TPs particularly for methylone and mephedrone can be used as potential target biomarkers for WBE studies due to their specificity and detectability within a 24h residence time.
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http://dx.doi.org/10.1016/j.scitotenv.2018.03.253DOI Listing
September 2018

Comparison of phosphodiesterase type V inhibitors use in eight European cities through analysis of urban wastewater.

Environ Int 2018 06 3;115:279-284. Epub 2018 Apr 3.

KWR Watercycle Research Institute, Chemical Water Quality and Health, P.O. Box 1072, 3430 BB Nieuwegein, The Netherlands; Institute for Biodiversity and Ecosystem Dynamics, University of Amsterdam, P.O. Box 94248, 1090 GE Amsterdam, The Netherlands. Electronic address:

In this work a step forward in investigating the use of prescription drugs, namely erectile dysfunction products, at European level was taken by applying the wastewater-based epidemiology approach. 24-h composite samples of untreated wastewater were collected at the entrance of eight wastewater treatment plants serving the catchment within the cities of Bristol, Brussels, Castellón, Copenhagen, Milan, Oslo, Utrecht and Zurich. A validated analytical procedure with direct injection of filtered aliquots by liquid chromatography-tandem mass spectrometry was applied. The target list included the three active pharmaceutical ingredients (sildenafil, tadalafil and vardenafil) together with (bio)transformation products and other analogues. Only sildenafil and its two human urinary metabolites desmethyl- and desethylsildenafil were detected in the samples with concentrations reaching 60 ng L. The concentrations were transformed into normalized measured loads and the estimated actual consumption of sildenafil was back-calculated from these loads. In addition, national prescription data from five countries was gathered in the form of the number of prescribed daily doses and transformed into predicted loads for comparison. This comparison resulted in the evidence of a different spatial trend across Europe. In Utrecht and Brussels, prescription data could only partly explain the total amount found in wastewater; whereas in Bristol, the comparison was in agreement; and in Milan and Oslo a lower amount was found in wastewater than expected from the prescription data. This study illustrates the potential of wastewater-based epidemiology to investigate the use of counterfeit medication and rogue online pharmacy sales.
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http://dx.doi.org/10.1016/j.envint.2018.03.039DOI Listing
June 2018

In vitro Phase I and Phase II metabolism of the new designer benzodiazepine cloniprazepam using liquid chromatography coupled to quadrupole time-of-flight mass spectrometry.

J Pharm Biomed Anal 2018 May 21;153:158-167. Epub 2018 Feb 21.

Toxicological Centre, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.

Designer benzodiazepines have recently emerged as a class of new psychoactive substances. These substances are used in recreational settings and as alternatives to prescription benzodiazepines as self-medication for patients suffering from anxiety or other mental disorders. Due to the limited information available on the metabolic fate of these new substances, it is challenging to reliably detect their usage in bioanalytical (e.g. clinical and forensic) settings. The objective of this study was to investigate the in vitro Phase I and Phase II metabolism of the new designer benzodiazepine cloniprazepam and identify potential biomarkers for its detection in human biological fluids. Cloniprazepam was incubated with human liver microsomes and cytosolic fractions to generate both Phase I and II metabolites. The extracts were analysed using liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. Identification of the metabolites was performed using two complementary workflows, including a suspect screening based on in silico predictions and a non-targeted screening. A total of nine metabolites were identified, eight Phase I metabolites and one Phase II metabolite, of which five were specific for cloniprazepam. Clonazepam was the major metabolite of cloniprazepam. Hydroxy-cloniprazepam, dihydroxy-cloniprazepam, 3-keto-cloniprazepam, 7-amino-cloniprazepam, hydroxy-clonazepam, 7-amino-clonazepam and 3-hydroxy-7-amino-clonazepam were formed through oxidation, hydroxylation, and/or reduction of the nitro-group. Glucuronidated hydroxy-cloniprazepam was the only Phase II metabolite detected. Five metabolites were specific for cloniprazepam. This study provided a set of human in vitro biotransformation products which can assist specific detection of cloniprazepam consumption in future studies.
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http://dx.doi.org/10.1016/j.jpba.2018.02.032DOI Listing
May 2018

Levamisole: a Common Adulterant in Cocaine Street Samples Hindering Electrochemical Detection of Cocaine.

Anal Chem 2018 04 2;90(8):5290-5297. Epub 2018 Mar 2.

AXES Research Group , University of Antwerp , Groenenborgerlaan 171 , 2020 Antwerp , Belgium.

The present work investigates the electrochemical determination of cocaine in the presence of levamisole, one of the most common adulterants found in cocaine street samples. Levamisole misleads cocaine color tests, giving a blue color (positive test) even in the absence of cocaine. Moreover, the electrochemical detection of cocaine is also affected by the presence of levamisole, with a suppression of the oxidation signal of cocaine. When levamisole is present in the sample in ratios higher than 1:1, the cocaine signal is no longer detected, thus leading to false negative results. Mass spectrometry and nuclear magnetic resonance were used to investigate if the signal suppression is due to the formation of a complex between cocaine and levamisole in bulk solution. Strategies to eliminate this suppressing effect are further suggested in this manuscript. In a first approach, the increase of the pH of the sample solution from pH 7 to pH 12 allowed the voltammetric determination of cocaine in the presence of levamisole in a concentration range from 10 to 5000 μM at nonmodified graphite disposable electrodes with a detection limit of 5 μM. In a second approach, the graphite electrode was cathodically pretreated, resulting in the presence of oxidation peaks of both cocaine and levamisole, with a detection limit for cocaine of 3 μM over the linear range of concentrations from 10 to 2500 μM. Both these strategies have been successfully applied for the simultaneous detection of cocaine and levamisole in three street samples on unmodified graphite disposable electrodes.
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http://dx.doi.org/10.1021/acs.analchem.8b00204DOI Listing
April 2018