Enantiomeric profiling of a chemically diverse mixture of chiral pharmaceuticals in urban water

Abstract

Due to concerns regarding the release of pharmaceuticals into the environment and the understudied impact of stereochemistry of pharmaceuticals on their fate and biological potency, we focussed in this paper on stereoselective transformation pathways of selected chiral pharmaceuticals (16 pairs) at both microcosm (receiving waters and activated sludge wastewater treatment simulating microcosms) and macrocosm (wastewater treatment plant (WWTP) utilising activated sludge technology and receiving waters) scales in order to test the hypothesis that biodegradation of chiral drugs is stereoselective. Our monitoring programme of a full scale activated sludge WWTP and receiving environment revealed that several chiral drugs, those being marketed mostly as racemates, are present in wastewater and receiving waters enriched with one enantiomeric form (e.g. fluoxetine, mirtazapine, salbutamol, MDMA). This is most likely due to biological metabolic processes occurring in humans and other organisms. Both activated sludge and receiving waters simulating microcosms confirmed our hypothesis that chiral drugs are subject to stereoselective microbial degradation. It led, in this research, to preferential degradation of S-(+)-enantiomers of amphetamines, R-(+)-enantiomers of beta-blockers and S-(+)-enantiomers of antidepressants. In the case of three parent compound - metabolite pairs (venlafaxine - desmethylvenlafaxine, citalopram - desmethylcitalopram and MDMA - MDA), while parent compounds showed higher resistance to both microbial metabolism and photodegradation, their desmethyl metabolites showed much higher degradation rate both in terms of stereoselective metabolic and non-stereoselective photochemical processes. It is also worth noting that metabolites tend to be, as expected, enriched with enantiomers of opposite configuration to their parent compounds, which might have significant toxicological consequences when evaluating the metabolic residues of chiral pollutants.

Chiral Analysis of Pesticides and Drugs of Environmental Concern: Biodegradation and Enantiomeric Fraction

“…Amorim et al observed enantioselective removal of norfluoxetine (metabolite of fluoxetine) in an AGS-SBR experiment and variations of the compound EF throughout the different operational phases of the reactor. Enantioselective degradation of metabolites of venlafaxine, citalopram, and MDMA was reported in two recent studies [75,82]. Degradation of the metabolite O-desmethylvenlafaxine exhibited notable enantiomeric enrichment under aerobic conditions and none under anaerobic conditions, contrary to the results obtained for the parent compound, which involved only slight stereoisomeric selectivity [75].…”

“…EF assessment during biodegradation experiments is crucial to understanding the stereoselectivity, concerning degradative routes and elimination and/or enrichment of the target enantiomers. Biodegradation studies with pharmaceuticals and drugs of abuse are usually designed for laboratory batch incubation experiments [75][76][77][78] or laboratory-scale bioreactors [79][80][81][82]. Enantioselective studies with constructed wetlands have also been reported [83].…”

“…Table 1 shows enantioselective biodegradation studies of chiral drugs in different environmental matrices and the chiral analytical techniques used to assess the EF during degradation, published between 1999 and 2017. In the original papers [8,10,[75][76][77][78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93], 22 different compounds from nine different drug classes are mentioned, including anti-inflammatory agents, antidepressants, and beta-blockers as the three most represented classes (Figure 2). Concerning the analytical methods used to quantify the enantiomers during biodegradation, a clear trend is observed.…”

“…Both works were followed by LC-FD and LC-MS/MS with a Chirobiotic™ R CSP under reverse-phase mode and isocratic elution, using 0.45% triethylamine aqueous solution (pH 3. Different studies have considered metabolites originating during the biodegradation of chiral compounds [75,82,84,91,93]. Matamoros et al followed the formation of the two major human metabolites of ibuprofen during experiments with microalgae reactors (carboxy-ibuprofen and hydroxy-ibuprofen) [91].…”

Occurrence of Chiral Bioactive Compounds in the Aquatic Environment: A Review

“…Since 2010, a trend is being verified for the use of three types of CSPs: protein-based [68,69,[74][75][76][77]81,82,100,101], polysaccharide-based [54,55,78,79,102] and macrocyclic antibiotic-based CSPs [13,26,27,63,64,71-73, 76,78,88,91,103]. The first reports describing the use of macrocyclic antibiotic-based CSPs for environmental analysis were published in 2006-2007 [84,104], but its application was later intensely reported from 2010 [13,26,27,57,[71][72][73]76,78,86,87,90,93,94,103,105]. Other works were published using normal elution mode, namely for the study of beta-blockers in surface waters [78,79] and for the monitoring of enantioselective biodegradation of warfarin in soils [11].…”