{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T21:43:40Z","timestamp":1770327820903,"version":"3.49.0"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2020,2,27]],"date-time":"2020-02-27T00:00:00Z","timestamp":1582761600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,7,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>An increasing number of benzodiazepine-type compounds are appearing on the new psychoactive substances market. 8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (well known as flualprazolam) represents a potent \u2018designer benzodiazepine\u2019 that has been associated with sedation, loss of consciousness, memory loss and disinhibition. The aims of the present study were to tentatively identify flualprazolam metabolites using in vitro incubations with pooled human liver S9 fraction or HepaRG cells by means of liquid-chromatography-high resolution tandem mass spectrometry. Isozymes involved in phase I and II biotransformation were identified in vitro. Results were then confirmed using human biosamples of an 18-year old male who was admitted to the emergency department after suspected flualprazolam ingestion. Furthermore, the plasma concentration was determined using the standard addition method. Seven flualprazolam metabolites were tentatively identified. Several cytochrome P450 and UDP-glucuronosyltransferase isozymes, amongst them CYP3A4 and UGT1A4, were shown to be involved in flualprazolam biotransformation reactions, and an influence of polymorphisms as well as drug\u2013drug or drug\u2013food interactions cannot be excluded. Alpha-hydroxy flualprazolam glucuronide, 4-hydroxy flualprazolam glucuronide and the parent glucuronide were identified as most abundant signals in urine, far more abundant than the parent compound flualprazolam. These metabolites are thus recommended as urine-screening targets. If conjugate cleavage was performed during sample preparation, the corresponding phase I metabolites should be added as targets. Both hydroxy metabolites can also be recommended for blood screening. The flualprazolam plasma concentration determined in the intoxication case was as low as 8\u00a0\u03bcg\/L underlining the need of analytical methods with sufficient sensitivity for blood-screening purposes.<\/jats:p>","DOI":"10.1093\/jat\/bkaa019","type":"journal-article","created":{"date-parts":[[2020,2,25]],"date-time":"2020-02-25T20:13:35Z","timestamp":1582661615000},"page":"549-558","source":"Crossref","is-referenced-by-count":24,"title":["Toxicokinetics and Analytical Toxicology of Flualprazolam: Metabolic Fate, Isozyme Mapping, Human Plasma Concentration and Main Urinary Excretion Products"],"prefix":"10.1093","volume":"44","author":[{"given":"Lea","family":"Wagmann","sequence":"first","affiliation":[{"name":"Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, Kirrberger Str. Geb. 46, 66421 Homburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sascha K","family":"Manier","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, Kirrberger Str. Geb. 46, 66421 Homburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas P","family":"Bambauer","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, Kirrberger Str. Geb. 46, 66421 Homburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christina","family":"Felske","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, Kirrberger Str. Geb. 46, 66421 Homburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Niels","family":"Eckstein","sequence":"additional","affiliation":[{"name":"Department of Applied Pharmacy, University of Applied Sciences Kaiserslautern, Campus Pirmasens, Carl-Schurz-Str. 10-16, 66953 Pirmasens, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Veit","family":"Flockerzi","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, Kirrberger Str. Geb. 46, 66421 Homburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Markus R","family":"Meyer","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, Kirrberger Str. Geb. 46, 66421 Homburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,2,27]]},"reference":[{"key":"2020073105271325700_ref1","volume-title":"World Drug Report 2018. 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Geneva, 21\u201325 October 2019","author":"World Health Organization"},{"key":"2020073105271325700_ref7","doi-asserted-by":"crossref","first-page":"66","DOI":"10.3109\/15563650.2015.1112907","article-title":"Flubromazolam\u2014a new life-threatening designer benzodiazepine","volume":"54","author":"Lukasik-Glebocka","year":"2016","journal-title":"Clinical Toxicology (Philadelphia)"},{"key":"2020073105271325700_ref8","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1007\/s11419-019-00501-1","article-title":"Identification of the designer benzodiazepine 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (flualprazolam) in an anesthesia robbery case","volume":"38","author":"Qian","year":"2019","journal-title":"Forensic Toxicology"},{"key":"2020073105271325700_ref9","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1002\/dta.2003","article-title":"Detectability of designer benzodiazepines in CEDIA, EMIT II Plus, HEIA, and KIMS II 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