title: Transformation of methadone and its main human metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), during water chlorination.
abstract: The reaction kinetics and reaction pathway of methadone and its main human metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) in chlorine containing waters were investigated by direct injection of individual reaction time aliquots in a liquid chromatography-quadrupole-time-of-flight-mass spectrometry (LC-QTOF-MS) system. Factors potentially affecting the rate of the reaction were evaluated in detail by means of a Box-Behnken experimental design in which methadone and EDDP were considered separately. Sample pH and chlorine concentration turned out to be the two significant variables, enhancing the kinetics with an increase in their values. Transformation products (TPs) were first searched over sample chromatograms by comparing control, blank and time zero samples to aliquots stopped at different reaction times. Their tentative identity was further inferred by generating their empirical formulae from their accurate single MS spectra and, subsequently, by interpreting their fragmentation pattern from their tandem MS (MS/MS) spectra. In total, 8 TPs, arising from intra-molecular cyclation, dehydrogenation, oxidation and chlorination, could be detected in the case of methadone, one of them being the EDDP and another 3 coming from EDDP, so being common to both the precursor drug and its metabolite. A tentative transformation pathway was proposed, and the reaction was evaluated under potential real circumstances by chlorinating two different river samples. In this way, it was possible to demonstrate that its extension is highly affected by the content of dissolved organic matter, so both compounds were highly or completely transformed in samples with a low anthropogenic impact, whereas they were considerably more stable in waters with a high concentration of organic matter. Finally, the ecotoxicity of precursors and transformation species was predicted by software tools, revealing that, in some cases, the toxicological responses displayed by the TPs were up to 100 times higher than those of methadone.
authors.affiliation: Department of Environmental Health Sciences, Mario Negri Institute for Pharmacological Research, Via G. La Masa 19, 20156 Milan, Italy. iria.gonzalezmarino@marionegri.it
authors.forename: Iria
authors.initials: I
authors.lastname: González-Mariño
authors.forename: José Benito
authors.initials: JB
authors.lastname: Quintana
authors.forename: Isaac
authors.initials: I
authors.lastname: Rodríguez
authors.forename: Miriam
authors.initials: M
authors.lastname: Cores
authors.forename: Rafael
authors.initials: R
authors.lastname: Cela
mesh_terms: D000701:Analgesics, Opioid / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D002713:Chlorine / Q000378:metabolism*; D002853:Chromatography, Liquid; D003530:Cyprinidae / Q000254:growth & development; D003621:Daphnia / Q000187:drug effects / Q000254:growth & development; D005618:Fresh Water / Q000737:chemistry; D054879:Halogenation; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D013058:Mass Spectrometry / Q000379:methods; D008691:Methadone / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D015394:Molecular Structure; D011759:Pyrrolidines / Q000737:chemistry / Q000378:metabolism*; D045483:Rivers / Q000737:chemistry; D018675:Toxicity Tests; D014865:Waste Disposal, Fluid / Q000379:methods; D014867:Water / Q000737:chemistry / Q000378:metabolism*; D014874:Water Pollutants, Chemical / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity
chemical_list: D000701:Analgesics, Opioid; D011759:Pyrrolidines; D014874:Water Pollutants, Chemical; D014867:Water; D002713:Chlorine; D008691:Methadone; C010724:2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine