A new approach towards biomarker selection in estimation of human exposure to chiral chemicals: a case study of mephedrone

Abstract

Wastewater-based epidemiology is an innovative approach to estimate public health status using biomarker analysis in wastewater. A new compound detected in wastewater can be a potential biomarker of an emerging trend in public health. However, it is currently difficult to select new biomarkers mainly due to limited human metabolism data. This manuscript presents a new framework, which enables the identification and selection of new biomarkers of human exposure to drugs with scarce or unknown human metabolism data. Mephedrone was targeted to elucidate the assessment of biomarkers for emerging drugs of abuse using a four-step analytical procedure. This framework consists of: (i) identification of possible metabolic biomarkers present in wastewater using an in-vivo study; (ii) verification of chiral signature of the target compound; (iii) confirmation of human metabolic residues in in-vivo/vitro studies and (iv) verification of stability of biomarkers in wastewater. Mephedrone was selected as a suitable biomarker due to its high stability profile in wastewater. Its enantiomeric profiling was studied for the first time in biological and environmental matrices, showing stereoselective metabolism of mephedrone in humans. Further biomarker candidates were also proposed for future investigation: 4′-carboxy-mephedrone, 4′-carboxy-normephedrone, 1-dihydro-mephedrone, 1-dihydro-normephedrone and 4′-hydroxy-normephedrone.

Stereochemistry of phase-1 metabolites of mephedrone determines their effectiveness as releasers at the serotonin transporter

“…In the case of nor-mephedrone we found that the S-enantiomer is almost 2 times more abundant in the human urine sample compared to its R-counterpart; hence, normephedrone is predominantly excreted in its S-enantiomeric form. This novel finding is in excellent agreement with a recent report (Castrignano et al, 2017). Previously, we found that systemically administered nor-mephedrone exerts profound effects on extracellular serotonin, whereas the effects were less pronounced for dopamine (Mayer et al, 2016).…”

“…A recent study revealed that mephedrone undergoes stereospecific metabolism and the stereoisomers of nor-and 4-OH-mephedrone were detected in biological samples (Castrignano et al, 2017). Based on the differing potencies as inhibitors of SERTmediated uptake, we sought to perform release experiments with the stereoisomers of nor-and 4-OH-mephedrone in SERT-expressing HEK293 cells.…”

“…no selectivity for SERT (Baumann et al, 2012), it is tempting to speculate that some of the subjective effects are linked to S-nor-mephedrone. This interpretation is bolstered by the fact that R-mephedrone appears to be the predominant stereoisomer in human samples and waste water (Castrignano et al, 2017). R-mephedrone shows greater selectivity for DAT over SERT than S-mephedrone.…”

“…Systemic administration of the N-demethylated metabolite nor-mephedrone results in a profound increase in extracellular serotonin but has only blunted effects on extracellular dopamine in nucleus accumbens (Mayer et al, 2016). Recently, stereospecific metabolism of mephedrone was reported (Castrignano et al, 2017). We therefore hypothesized that stereospecific pharmacokinetics and pharmacodynamics of the phase-1 metabolites may contribute to the overall effects of mephedrone.…”

Enantiomeric profiling of chiral illicit drugs in a pan-European study

“…Furthermore, mephedrone was found to be enriched with the R-(+)-enantiomer in wastewater (EFww in 2014 (n=6)=0.57±0.02 and EFww in 2015 (n=4)=0.57±0.04). This indicates that mephedrone was consumed rather than directly disposed (Castrignanò, Mardal et al 2017) (see section S4 for further information).…”