Comparison of the Metabolic Profiles Associated with Protonitazene and Protonitazepyne in Two Severe Poisonings
Nitazenes represent an emerging class of new synthetic opioids characterized by a high-potency μ-opioid receptor (MOR) agonist activity. <b>Background</b>: We report two 20-year-old males who presented with severe neurorespiratory depression with typical opioid syndrome, but no opioid id...
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2025-06-01
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| author | Romain Magny Thomas Schiestel Aymen M’Rad Bertrand Lefrère Jean-Herlé Raphalen Stanislas Ledochowski Laurence Labat Bruno Mégarbane Pascal Houzé |
| author_facet | Romain Magny Thomas Schiestel Aymen M’Rad Bertrand Lefrère Jean-Herlé Raphalen Stanislas Ledochowski Laurence Labat Bruno Mégarbane Pascal Houzé |
| author_sort | Romain Magny |
| collection | DOAJ |
| description | Nitazenes represent an emerging class of new synthetic opioids characterized by a high-potency μ-opioid receptor (MOR) agonist activity. <b>Background</b>: We report two 20-year-old males who presented with severe neurorespiratory depression with typical opioid syndrome, but no opioid identification based on routine blood and urine screening tests. The first patient recovered with supportive care, mechanical ventilation, and naloxone infusion, whereas the second patient developed post-anoxic cardiac arrest and died from brain death. <b>Methods</b>: A complementary comprehensive toxicological screening using liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS) was performed, and data were processed using a dedicated molecular network strategy to profile the metabolites. <b>Results</b>: Protonitazene and protonitazepyne, two nitazenes differing in their ethylamine moieties (i.e., a diethyl versus a pyrrolidine substitution, respectively), were identified. We found an extensive metabolism of protonitazene, leading to the identification of multiple phase I (resulting from hydroxylation, N-desethylation, and O-despropylation) and phase II (resulting from glucuronidation) metabolites. By contrast, protonitazepyne metabolism appeared limited, with one metabolite annotated confidently, protonitazepyne acid, which resulted from the oxidative pyrrolidine ring cleavage. <b>Concusions</b>: To conclude, nitazene detection is highly challenging due to its extensive structural and metabolic diversity. Our findings highlight the contribution of the untargeted LC-HRMS screening approach and suggest that diagnostic product ions can serve as robust markers for nitazene identification. |
| format | Article |
| id | doaj-art-a6a91cab74f8422983b9fe401afa8827 |
| institution | DOAJ |
| issn | 2218-1989 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Metabolites |
| spelling | doaj-art-a6a91cab74f8422983b9fe401afa88272025-08-20T03:16:19ZengMDPI AGMetabolites2218-19892025-06-0115637110.3390/metabo15060371Comparison of the Metabolic Profiles Associated with Protonitazene and Protonitazepyne in Two Severe PoisoningsRomain Magny0Thomas Schiestel1Aymen M’Rad2Bertrand Lefrère3Jean-Herlé Raphalen4Stanislas Ledochowski5Laurence Labat6Bruno Mégarbane7Pascal Houzé8Laboratoire de Toxicologie, Fédération de Toxicologie, Hôpital Lariboisière, AP-HP, 75010 Paris, FranceLaboratoire de Toxicologie, Fédération de Toxicologie, Hôpital Lariboisière, AP-HP, 75010 Paris, FranceRéanimation Médicale et Toxicologique, Fédération de Toxicologie, Hôpital Lariboisière, AP-HP, 75010 Paris, FranceService de Biochimie Générale, Hôpital Necker-Enfants Malades, AP-HP, 75015 Paris, FranceDepartment of Anesthesiology and Intensive Care Medicine, Adult Intensive Care Unit, Necker Hospital, 75015 Paris, FranceService de Réanimation Polyvalente, Médipôle Lyon-Villeurbanne, Ramsay Santé, 69100 Villeurbanne, FranceLaboratoire de Toxicologie, Fédération de Toxicologie, Hôpital Lariboisière, AP-HP, 75010 Paris, FranceINSERM, Université Paris-Cité, Optimisation Thérapeutique en Neuropharmacologie OTEN U1144, 75006 Paris, FranceLaboratoire de Toxicologie, Fédération de Toxicologie, Hôpital Lariboisière, AP-HP, 75010 Paris, FranceNitazenes represent an emerging class of new synthetic opioids characterized by a high-potency μ-opioid receptor (MOR) agonist activity. <b>Background</b>: We report two 20-year-old males who presented with severe neurorespiratory depression with typical opioid syndrome, but no opioid identification based on routine blood and urine screening tests. The first patient recovered with supportive care, mechanical ventilation, and naloxone infusion, whereas the second patient developed post-anoxic cardiac arrest and died from brain death. <b>Methods</b>: A complementary comprehensive toxicological screening using liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS) was performed, and data were processed using a dedicated molecular network strategy to profile the metabolites. <b>Results</b>: Protonitazene and protonitazepyne, two nitazenes differing in their ethylamine moieties (i.e., a diethyl versus a pyrrolidine substitution, respectively), were identified. We found an extensive metabolism of protonitazene, leading to the identification of multiple phase I (resulting from hydroxylation, N-desethylation, and O-despropylation) and phase II (resulting from glucuronidation) metabolites. By contrast, protonitazepyne metabolism appeared limited, with one metabolite annotated confidently, protonitazepyne acid, which resulted from the oxidative pyrrolidine ring cleavage. <b>Concusions</b>: To conclude, nitazene detection is highly challenging due to its extensive structural and metabolic diversity. Our findings highlight the contribution of the untargeted LC-HRMS screening approach and suggest that diagnostic product ions can serve as robust markers for nitazene identification.https://www.mdpi.com/2218-1989/15/6/371protonitazenenitazenenew synthetic opioidhigh resolution mass spectrometrymolecular network |
| spellingShingle | Romain Magny Thomas Schiestel Aymen M’Rad Bertrand Lefrère Jean-Herlé Raphalen Stanislas Ledochowski Laurence Labat Bruno Mégarbane Pascal Houzé Comparison of the Metabolic Profiles Associated with Protonitazene and Protonitazepyne in Two Severe Poisonings Metabolites protonitazene nitazene new synthetic opioid high resolution mass spectrometry molecular network |
| title | Comparison of the Metabolic Profiles Associated with Protonitazene and Protonitazepyne in Two Severe Poisonings |
| title_full | Comparison of the Metabolic Profiles Associated with Protonitazene and Protonitazepyne in Two Severe Poisonings |
| title_fullStr | Comparison of the Metabolic Profiles Associated with Protonitazene and Protonitazepyne in Two Severe Poisonings |
| title_full_unstemmed | Comparison of the Metabolic Profiles Associated with Protonitazene and Protonitazepyne in Two Severe Poisonings |
| title_short | Comparison of the Metabolic Profiles Associated with Protonitazene and Protonitazepyne in Two Severe Poisonings |
| title_sort | comparison of the metabolic profiles associated with protonitazene and protonitazepyne in two severe poisonings |
| topic | protonitazene nitazene new synthetic opioid high resolution mass spectrometry molecular network |
| url | https://www.mdpi.com/2218-1989/15/6/371 |
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