Tentative identification of the phase I and II metabolites of two synthetic cathinones, MDPHP and α-PBP, in human urine.
LC-HRMS/MS
MDPHP
human urine
metabolite
α-PBP
Journal
Drug testing and analysis
ISSN: 1942-7611
Titre abrégé: Drug Test Anal
Pays: England
ID NLM: 101483449
Informations de publication
Date de publication:
Oct 2020
Oct 2020
Historique:
received:
11
04
2020
revised:
21
06
2020
accepted:
30
06
2020
pubmed:
6
7
2020
medline:
27
8
2021
entrez:
5
7
2020
Statut:
ppublish
Résumé
Cathinone derivatives are one of the more prominent groups of new psychoactive substances in terms of the number of forensic case reports and the variety of chemical structures available. These substances often sold as "bath salts" are classified as psychostimulants. Using liquid chromatography-high resolution mass spectrometry, the metabolites of two pyrrolidine cathinone derivatives, α-PBP and the less common MDPHP, were tentatively identified in urine samples collected from patients admitted to hospital following drug intoxications. The major metabolic pathways for α-PBP and MDPHP were similar to those of their more common analogs (α-PVP and MDPV). Metabolites arising from hydroxylation, reduction of the carbonyl group to an alcohol, oxidation to form a lactam and subsequent ring-opening, and a combination of these processes were identified. In addition, biotransformations of the benzodioxole moiety in MDPHP included demethylenation with subsequent methylation and carboxylation of the butyl group. The majority of the hydroxylated metabolites of α-PBP and MDPHP were found to be glucuronidated. Both α-PBP and MDPHP undergo extensive metabolism and the chromatographic peak areas of the metabolites were found to be comparable to or exceeded those of the parent substances. Metabolites resulting from demethylenation and subsequent methylation (MDPHP), reduction of carbonyl group (α-PBP), and oxidation to form a lactam combined with ring-opening (α-PBP and MDPHP) were found to be the most useful target analytes for the confirmation of ingestion.
Substances chimiques
Alkaloids
0
Psychotropic Drugs
0
cathinone
540EI4406J
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1442-1451Informations de copyright
© 2020 John Wiley & Sons, Ltd.
Références
EMCDDA. European Drug Report: Trends and Developments 2019. https://www.emcdda.europa.eu/system/files/publications/11364/20191724_TDAT19001ENN_PDF.pdf. Accessed 31 March 2020.
Koeppe H, Zeile K, Ludwig G. Germany Patent Application - Verfahren zur Herstellung von alpha-Aminoketonen mit heterocyclischer Aminogruppe. Germany Patent No. DE1545591, 1965.
Thomae K. UK patent application - α-Pyrrolidino-ketones. UK Patent no 933507, 1963.
EMCDDA-Europol. 2014. Annual Report on the implementation of Council Decision 20142005/387/JHA. http://www.emcdda.europa.eu/system/files/publications/1018/TDAN15001ENN.pdf. Accessed 31 March 2020.
EMCDDA-Europol. 2011. Annual Report on the implementation of Council Decision 2005/387/JHA. http://www.emcdda.europa.eu/system/files/publications/689/EMCDDA-Europol_Annual_Report_2011_2012_final_335568.pdf. Accessed 31 March 2020.
Zaitsu K, Katagi M, Tsuchihashi H, Ishii A. Recently abused synthetic cathinones, α-pyrrolidinophenone derivatives: a review of their pharmacology, acute toxicity, and metabolism. Forensic Toxicol. 2014;32(1):1-8. https://doi.org/10.1007/s11419-013-0218-1
Eshleman AJ, Nagarajan S, Wolfrum KM, et al. Structure-activity relationships of bath salt components: substituted cathinones and benzofurans at biogenic amine transporters. Psychopharmacology (Berl). 2019;236(3):939-952. https://doi.org/10.1007/s00213-018-5059-5
Banks ML, Worst TJ, Sprague JE. Synthetic cathinones and amphetamine analogues: What’s the rave about? J Emerg Med. 2014;46(5):632-642. https://doi.org/10.1016/j.jemermed.2013.11.104
Hardy G, Stoddard E, Dunn M, Hill SL, Thomas SHL. Clinical toxicity from analytically confirmed exposure to the synthetic cathinone methylenedioxy pyrrolidinohexiophenone (MDPHP) in the UK. Clin Toxicol. 2019;57(6):439-440. https://doi.org/10.1080/15563650.2019.1598646
Adamowicz P, Hydzik P. Fetal death associated with the use of 3,4-MDPHP and α-PHP. Clin Toxicol. 2019;57(2):112-116. https://doi.org/10.1080/15563650.2018.1502443
Carlsson A, Sandgren V, Svensson S, et al. Prediction of designer drugs: synthesis and spectroscopic analysis of synthetic cathinone analogs that may appear on the Swedish drug market. Drug Test Anal. 2018;10(7):1076-1098. https://doi.org/10.1002/dta.2366
Kaizaki-Mitsumoto A, Noguchi N, Yamaguchi S, et al. Three 25-NBOMe-type drugs, three other phenethylamine-type drugs (25I-NBMD, RH34, and escaline), eight cathinone derivatives, and a phencyclidine analog MMXE, newly identified in ingredients of drug products before they were sold on the drug market. Forensic Toxicol. 2016;34(1):108-114. https://doi.org/10.1007/s11419-015-0293-6
Namera A, Urabe S, Saito T, et al. A fatal case of 3,4-methylenedioxypyrovalerone poisoning: coexistence of α-pyrrolidinobutiophenone and α-pyrrolidinovalerophenone in blood and/or hair. Forensic Toxicol. 2013;31(2):338-343. https://doi.org/10.1007/s11419-013-0192-7
Uralets V, Rana S, Morgan S, Ross W. Testing for designer stimulants: metabolic profiles of 16 synthetic cathinones excreted free in human urine. J Anal Toxicol. 2014;38(5):233-241. https://doi.org/10.1093/jat/bku021
Woźniak MK, Banaszkiewicz L, Wiergowski M, et al. Development and validation of a GC-MS/MS method for the determination of 11 amphetamines and 34 synthetic cathinones in whole blood. Forensic Toxicol. 2020;38(1):42-58. https://doi.org/10.1007/s11419-019-00485-y
Bäckberg M, Jönsson K-H, Helander A, Beck O. Investigation of drug products received for analysis in the Swedish STRIDA project on new psychoactive substances. Drug Test Anal. 2018;10(2):340-349. https://doi.org/10.1002/dta.2226
Wurita A, Hasegawa K, Minakata K, et al. Postmortem distribution of α-pyrrolidinobutiophenone in body fluids and solid tissues of a human cadaver. Leg Med. 2014;16(5):241-246. https://doi.org/10.1016/j.legalmed.2014.05.001
Boumba VA, Rago MD, Peka M, Drummer OH, Gerostamoulos D. The analysis of 132 novel psychoactive substances in human hair using a single step extraction by tandem LC/MS. Forensic Sci Int. 2017;279:192-202. https://doi.org/10.1016/j.forsciint.2017.08.031.19
Beck O, Bäckberg M, Signell P, Helander A. Intoxications in the STRIDA project involving a panorama of psychostimulant pyrovalerone derivatives, MDPV copycats. Clin Toxicol. 2018;56(4):256-263. https://doi.org/10.1080/15563650.2017.1370097
Sorribes-Soriano A, Esteve-Turrillas FA, Armenta S, Amorós P, Herrero-Martínez JM. Amphetamine-type stimulants analysis in oral fluid based on molecularly imprinting extraction. Anal Chim Acta. 2019;1052:73-83. https://doi.org/10.1016/j.aca.2018.11.046
Franzén L, Bäckberg M, Beck O, Helander A. Acute intoxications involving α-pyrrolidinobutiophenone (α-PBP): results from the Swedish STRIDA project. J Med Toxicol. 2018;14(4):265-271. https://doi.org/10.1007/s13181-018-0668-2
Niebel A, Krumbiegel F, Hartwig S, Parr MK, Tsokos M. Detection and quantification of synthetic cathinones and selected piperazines in hair by LC-MS/MS. Forensic Sci Med Pathol. 2020;16(1):32-42. https://doi.org/10.1007/s12024-019-00209-z
Richeval C, Phanithavong M, Humbert L, et al. Identification des métabolites de la méthylènedioxy-α-pyrrolidinohexanophénone (MDPHP) et données de concentrations dans les poils corporels: à propos d'un cas d'intoxication d'un slameur. Toxicol Anal Clin. 2019;31(2):S42. https://doi.org/10.1016/j.toxac.2019.03.056 (France)
Grapp M, Kaufmann C, Schwelm HM, Neukamm MA, Blaschke S, Eidizadeh A. Intoxication cases associated with the novel designer drug 3′,4′-methylenedioxy-α-pyrrolidinohexanophenone (MDPHP) and studies on its human metabolism by high-resolution mass spectrometry. Drug Test Anal. 2020. https://doi.org/10.1002/dta.2869
Matsuta S, Shima N, Kamata H, et al. Metabolism of the designer drug α-pyrrolidinobutiophenone (α-PBP) in humans: identification and quantification of the phase I metabolites in urine. Forensic Sci Int. 2015;249:181-188. https://doi.org/10.1016/j.forsciint.2015.02.004
Namera A, Konuma K, Kawamura M, et al. Time-course profile of urinary excretion of intravenously administered α-pyrrolidinovalerophenone and α-pyrrolidinobutiophenone in a human. Forensic Toxicol. 2014;32(1):68-74. https://doi.org/10.1007/s11419-013-0203-8
Ibáñez M, Pozo ÓJ, Sancho JV, Orengo T, Haro G, Hernández F. Analytical strategy to investigate 3,4-methylenedioxypyrovalerone (MDPV) metabolites in consumers’ urine by high-resolution mass spectrometry. Anal Bioanal Chem. 2016;408(1):151-164. https://doi.org/10.1007/s00216-015-9088-1
Meyer MR, Du P, Schuster F, Maurer HH. Studies on the metabolism of the α-pyrrolidinophenone designer drug methylenedioxy-pyrovalerone (MDPV) in rat and human urine and human liver microsomes using GC-MS and LC-high-resolution MS and its detectability in urine by GC-MS. J Mass Spectrom. 2010;45(12):1426-1442. https://doi.org/10.1002/jms.1859
Grapp M, Kaufmann C, Ebbecke M. Toxicological investigation of forensic cases related to the designer drug 3,4-methylenedioxypyrovalerone (MDPV): detection, quantification and studies on human metabolism by GC-MS. Forensic Sci Int. 2017;243:1-9. https://doi.org/10.1016/j.forsciint.2017.01.021
Zaikina OL, Shilov VV, Lodyagin AN, Glushkov SI, Grigoryev AM. Determination of the structures of free and glucuronidated metabolites of α-pyrrolidinovalerophenone in human urine by liquid chromatography-mass spectrometry with accurate mass measurement. J Analyt Chem. 2019;74(5):489-504. https://doi.org/10.1134/S1061934819020138
Negreira N, Erratico C, Kosjek T, et al. In vitro phase I and phase II metabolism of α-pyrrolidinovalerophenone (α-PVP), methylenedioxypyrovalerone (MDPV) and methedrone by human liver microsomes and human liver cytosol. Anal Bioanal Chem. 2015;407(19):5803-5816. https://doi.org/10.1007/s00216-015-8763-6
Apirakkan O, Frinculescu A, Shine T, et al. Analytical characterization of three cathinone derivatives, 4-MPD, 4F-PHP and bk-EPDP, purchased as bulk powder from online vendors. Drug Test Anal. 2018;10(2):372-378. https://doi.org/10.1002/dta.2218
Fornal E. Study of collision-induced dissociation of electrospray-generated protonated cathinones. Drug Test Anal. 2014;6(7-8):705-715. https://doi.org/10.1002/dta.1573
Shevyrin V, Eltsov O, Shafran Y. Identification and analytical characterization of the synthetic cathinone N-butylhexedrone. Drug Test Anal. 2020;12(1):159-163. https://doi.org/10.1002/dta.2712