{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T01:58:10Z","timestamp":1790128690877,"version":"4.0.1"},"reference-count":40,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T00:00:00Z","timestamp":1718668800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Saarland University and the German Research Foundation DFG","award":["477298507"],"award-info":[{"award-number":["477298507"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>With a rising demand of cocaine over the last years, it is likely that unregulated new psychoactive substances with similar effects such as indatraline ((1R,3S)-3-(3,4-dichlorophenyl)-N-methyl-2,3-dihydro-1H-inden-1-amine) and troparil (Methyl (1R,2S,3S,5S)-8-methyl-3-phenyl-8-azabicyclo[3.2.1]octane-2-carboxylate) become popular as well. Both substances share a similar pharmacological profile as cocaine, while their potency is higher, and their duration of action is longer. This study investigated their metabolic fate in rat urine and incubations using pooled human liver S9 fraction (pHLS9). Indatraline formed two phase I and four phase II metabolites, with aromatic hydroxylation and glucuronidation being the main metabolic steps. All metabolites were detected in rat urine, while the parent compound was not detectable. Although low in abundance, indatraline metabolites were well identifiable due to their specific isotopic patterns caused by chlorine. Troparil formed four phase I and three phase II metabolites, with demethylation being the main metabolic step. Hydroxylation of the tropane ring, the phenyl ring, and combinations of these steps, as well as glucuronidation, were found. Phase I metabolites were detectable in rat urine and pHLS9, while phase II metabolites were only detectable in rat urine.<\/jats:p>","DOI":"10.3390\/metabo14060342","type":"journal-article","created":{"date-parts":[[2024,6,19]],"date-time":"2024-06-19T04:21:28Z","timestamp":1718770888000},"page":"342","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Characterization and Metabolism of Drug Products Containing the Cocaine-Like New Psychoactive Substances Indatraline and Troparil"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7126-5263","authenticated-orcid":false,"given":"Sascha K.","family":"Manier","sequence":"first","affiliation":[{"name":"Department of Experimental and Clinical Toxicology and Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, Center for Molecular Signaling (PZMS), 66421 Homburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Mumber","sequence":"additional","affiliation":[{"name":"Applied Pharmacy, University of Applied Sciences Kaiserslautern, Campus Pirmasens, 66953 Pirmasens, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josef","family":"Zapp","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Biology, Saarland University, 66123 Saarbr\u00fccken, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niels","family":"Eckstein","sequence":"additional","affiliation":[{"name":"Applied Pharmacy, University of Applied Sciences Kaiserslautern, Campus Pirmasens, 66953 Pirmasens, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4377-6784","authenticated-orcid":false,"given":"Markus R.","family":"Meyer","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Toxicology and Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, Center for Molecular Signaling (PZMS), 66421 Homburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,18]]},"reference":[{"key":"ref_1","unstructured":"UNODC (2023). World Drug Report 2023, UNODC."},{"key":"ref_2","unstructured":"UNODC (2023). World Drug Report 2023, UNODC."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.3389\/fphar.2018.01145","article-title":"Drug Interactions With New Synthetic Opioids","volume":"9","author":"Papaseit","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"34655","DOI":"10.1038\/srep34655","article-title":"Antidepressant indatraline induces autophagy and inhibits restenosis via suppression of mTOR\/S6 kinase signaling pathway","volume":"6","author":"Cho","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_5","first-page":"60","article-title":"Effects of the long-acting monoamine reuptake inhibitor indatraline on cocaine self-administration in rhesus monkeys","volume":"291","author":"Negus","year":"1999","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1021\/jm00269a600","article-title":"Compounds Affecting the Central Nervous System. 4. 3.beta.-Phenyltropane-2-carboxylic Esters and Analogs","volume":"16","author":"Clarke","year":"2003","journal-title":"J. Med. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1021\/jm00002a020","article-title":"Cocaine and 3.beta.-(4\u2032-Substituted phenyl)tropane-2.beta.-carboxylic Acid Ester and Amide Analogs. New High-Affinity and Selective Compounds for the Dopamine Transporter","volume":"38","author":"Carroll","year":"2002","journal-title":"J. Med. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4406","DOI":"10.1021\/jm970549h","article-title":"Synthesis, Structure, Dopamine Transporter Affinity, and Dopamine Uptake Inhibition of 6-Alkyl-3-benzyl-2-[(methoxycarbonyl)methyl]tropane Derivatives","volume":"40","author":"Lomenzo","year":"1997","journal-title":"J. Med. Chem."},{"key":"ref_9","first-page":"132","article-title":"Identification and structural characterization of three psychoactive substances, phenylpiperazines (pBPP and 3,4-CFPP) and a cocaine analogue (troparil), in collected samples","volume":"40","author":"Bednarek","year":"2021","journal-title":"Forensic Toxicol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.forsciint.2006.05.019","article-title":"Demands on scientific studies in clinical toxicology","volume":"165","author":"Maurer","year":"2007","journal-title":"Forensic Sci. Int."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.jpba.2017.05.028","article-title":"Pooled human liver preparations, HepaRG, or HepG2 cell lines for metabolism studies of new psychoactive substances? A study using MDMA, MDBD, butylone, MDPPP, MDPV, MDPB, 5-MAPB, and 5-API as examples","volume":"143","author":"Richter","year":"2017","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.toxlet.2017.07.901","article-title":"New psychoactive substances: Studies on the metabolism of XLR-11, AB-PINACA, FUB-PB-22, 4-methoxy-alpha-PVP, 25-I-NBOMe, and meclonazepam using human liver preparations in comparison to primary human hepatocytes, and human urine","volume":"280","author":"Richter","year":"2017","journal-title":"Toxicol. Lett."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Boutron, I., Percie du Sert, N., Ahluwalia, A., Alam, S., Avey, M.T., Baker, M., Browne, W.J., Clark, A., Cuthill, I.C., and Dirnagl, U. (2020). Reporting animal research: Explanation and elaboration for the ARRIVE guidelines 2.0. PLoS Biol., 18.","DOI":"10.1371\/journal.pbio.3000411"},{"key":"ref_14","unstructured":"Maurer, H.H., Pfleger, K., and Weber, A.A. (2016). Mass Spectral Library of Drugs, Poisons, Pesticides, Pollutants, and Their Metabolites, Wiley-VCH. [5th ed.]."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"692","DOI":"10.2174\/1570159X14666161018151716","article-title":"New Psychoactive Substances 3-Methoxyphencyclidine (3-MeO-PCP) and 3-Methoxyrolicyclidine (3-MeO-PCPy): Metabolic Fate Elucidated with Rat Urine and Human Liver Preparations and their Detectability in Urine by GC-MS, \u201cLC-(High Resolution)-MSn\u201d and \u201cLC-(High Resolution)-MS\/MS\u201d","volume":"15","author":"Michely","year":"2017","journal-title":"Curr. Neuropharmacol."},{"key":"ref_16","unstructured":"(2024, April 12). \u201cTroparil Erfahrungsbericht\u201d of user \u201cTodestrieb\u201d on eve&rave. Available online: https:\/\/www.eve-rave.ch\/Forum\/viewtopic.php?t=70400."},{"key":"ref_17","unstructured":"(2024, April 12). \u201cMeine Indatraline Erfahrung\u201d of user \u201cu\/11312\u201d on reddit. Available online: https:\/\/www.reddit.com\/r\/drogen\/comments\/x7ante\/meine_indatraline_erfahrung\/."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1111\/j.1476-5381.2009.00267.x","article-title":"To scale or not to scale: The principles of dose extrapolation","volume":"157","author":"Sharma","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3481","DOI":"10.1007\/s00216-011-5032-1","article-title":"Drugs of abuse screening in urine as part of a metabolite-based LC-MSn screening concept","volume":"400","author":"Wissenbach","year":"2011","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.aca.2015.08.018","article-title":"Orbitrap technology for comprehensive metabolite-based liquid chromatographic-high resolution-tandem mass spectrometric urine drug screening-exemplified for cardiovascular drugs","volume":"891","author":"Helfer","year":"2015","journal-title":"Anal. Chim. Acta."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Manier, S.K., Schwermer, F., Wagmann, L., Eckstein, N., and Meyer, M.R. (2020). Liquid Chromatography-High-Resolution Mass Spectrometry-Based In Vitro Toxicometabolomics of the Synthetic Cathinones 4-MPD and 4-MEAP in Pooled Human Liver Microsomes. Metabolites, 11.","DOI":"10.3390\/metabo11010003"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1097\/00007691-200204000-00009","article-title":"Toxicokinetics of amphetamines: Metabolism and toxicokinetic data of designer drugs, amphetamine, methamphetamine, and their N-alkyl derivatives","volume":"24","author":"Kraemer","year":"2002","journal-title":"Ther. Drug Monit."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"110304","DOI":"10.1016\/j.forsciint.2020.110304","article-title":"Purity estimation of seized stimulant-type new psychoactive substances without reference standards by nitrogen chemiluminescence detection combined with GC-APCI-QTOFMS","volume":"312","author":"Rasanen","year":"2020","journal-title":"Forensic Sci. Int."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1111\/add.13720","article-title":"Purity, adulteration and price of drugs bought on-line versus off-line in the Netherlands","volume":"112","author":"Brunt","year":"2017","journal-title":"Addiction"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Di Trana, A., Berardinelli, D., Montanari, E., Berretta, P., Basile, G., Huestis, M.A., and Busard\u00f2, F.P. (2022). Molecular Insights and Clinical Outcomes of Drugs of Abuse Adulteration: New Trends and New Psychoactive Substances. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232314619"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1002\/dta.2197","article-title":"Metabolism of the tryptamine-derived new psychoactive substances 5-MeO-2-Me-DALT, 5-MeO-2-Me-ALCHT, and 5-MeO-2-Me-DIPT and their detectability in urine studied by GC-MS, LC-MS(n), and LC-HR-MS\/MS","volume":"10","author":"Caspar","year":"2018","journal-title":"Drug Test. Anal."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1007\/s00216-017-0526-0","article-title":"LC-high resolution-MS\/MS for identification of 69 metabolites of the new psychoactive substance 1-(4-ethylphenyl-)-N-[(2-methoxyphenyl)methyl] propane-2-amine (4-EA-NBOMe) in rat urine and human liver S9 incubates and comparison of its screening power with further MS techniques","volume":"410","author":"Caspar","year":"2018","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"7831","DOI":"10.1007\/s00216-015-8955-0","article-title":"Metabolism of the new psychoactive substances N,N-diallyltryptamine (DALT) and 5-methoxy-DALT and their detectability in urine by GC-MS, LC-MSn, and LC-HR-MS-MS","volume":"407","author":"Michely","year":"2015","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1093\/jat\/bkz052","article-title":"Use of UPLC-HRMS\/MS for In Vitro and In Vivo Metabolite Identification of Three Methylphenidate-derived New Psychoactive Substances","volume":"44","author":"Manier","year":"2020","journal-title":"J. Anal. Toxicol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/S0041-008X(03)00128-5","article-title":"An update on in vitro test methods in human hepatic drug biotransformation research: Pros and cons","volume":"189","author":"Brandon","year":"2003","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_31","unstructured":"Maurer, H.H., Meyer, M.R., Pfleger, K., and Weber, A.A. (2023). GC-MS Library of Drugs, Poisons, and Their Metabolites, Wiley-VCH. [6th ed.]."},{"key":"ref_32","first-page":"542","article-title":"Metabolism and disposition of the 5-hydroxytryptamine uptake blocker sertraline in the rat and dog","volume":"17","author":"Tremaine","year":"1989","journal-title":"Drug Metab. Dispos."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1097\/00004850-199112002-00004","article-title":"Clinical implications of the pharmacology of sertraline","volume":"6","author":"Warrington","year":"1991","journal-title":"Int. Clin. Psychopharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.2165\/00003088-200241150-00002","article-title":"Clinical pharmacokinetics of sertraline","volume":"41","author":"DeVane","year":"2002","journal-title":"Clin. Pharmacokinet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"815","DOI":"10.2174\/138920007782798153","article-title":"The conduct of drug metabolism studies considered good practice (I): Analytical systems and in vivo studies","volume":"8","author":"Liu","year":"2007","journal-title":"Curr. Drug. Metab."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Sinz, M.A. (2012). In VitroandIn VivoModels of Drug Metabolism. Encyclopedia of Drug Metabolism and Interactions, John Wiley & Sons, Inc.","DOI":"10.1002\/9780470921920.edm002"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1080\/00498250601140072","article-title":"Drug-drug interactions in the metabolism of imidafenacin: Role of the human cytochrome P450 enzymes and UDP-glucuronic acid transferases, and potential of imidafenacin to inhibit human cytochrome P450 enzymes","volume":"37","author":"Kanayama","year":"2007","journal-title":"Xenobiotica"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Roque Bravo, R., Faria, A.C., Brito-da-Costa, A.M., Carmo, H., Mladenka, P., Dias da Silva, D., Remiao, F., and On Behalf Of The Oemonom, R. (2022). Cocaine: An Updated Overview on Chemistry, Detection, Biokinetics, and Pharmacotoxicological Aspects including Abuse Pattern. Toxins, 14.","DOI":"10.3390\/toxins14040278"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"23161","DOI":"10.1039\/D1RA04538E","article-title":"Efficient kinetic resolution in the asymmetric transfer hydrogenation of 3-aryl-indanones: Applications to a short synthesis of (+)-indatraline and a formal synthesis of (R)-tolterodine","volume":"11","author":"Park","year":"2021","journal-title":"RSC Adv."},{"key":"ref_40","unstructured":"Malz, F. (2003). Quantitative NMR-Spektroskopie als Referenzverfahren in der Analytischen Chemie. [Ph.D. Dissertation, Humboldt-Universit\u00e4t zu Berlin, Mathematisch-Naturwissenschaftliche Fakult\u00e4t I]."}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/14\/6\/342\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:00:44Z","timestamp":1760108444000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/14\/6\/342"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,18]]},"references-count":40,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2024,6]]}},"alternative-id":["metabo14060342"],"URL":"https:\/\/doi.org\/10.3390\/metabo14060342","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,18]]}}}