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Identifying Metabolites of Meclonazepam by High-Resolution Mass Spectrometry Using Human Liver Microsomes, Hepatocytes, a Mouse Model, and Authentic Urine Samples
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. National Board Forens Med, Department Forens Genet and Forens Toxicol, Linkoping, Sweden.
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. National Board Forens Med, Department Forens Genet and Forens Toxicol, Linkoping, Sweden.
National Board Forens Med, Department Forens Genet and Forens Toxicol, Linkoping, Sweden.
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. National Board Forens Med, Department Forens Genet and Forens Toxicol, Linkoping, Sweden.
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2017 (English)In: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 19, no 3, 736-742 p.Article in journal (Refereed) Published
Abstract [en]

Meclonazepam is a benzodiazepine patented in 1977 to treat parasitic worms, which recently appeared as a designer benzodiazepine and drug of abuse. The aim of this study was to identify metabolites suitable as biomarkers of drug intake in urine using high-resolution mass spectrometry, authentic urine samples, and different model systems including human liver microsomes, cryopreserved hepatocytes, and a mice model. The main metabolites of meclonazepam found in human urine were amino-meclonazepam and acetamido-meclonazepam; also, minor peaks for meclonazepam were observed in three of four urine samples. These observations are consistent with meclonazepam having a metabolism similar to that of other nitro containing benzodiazepines such as clonazepam, flunitrazepam, and nitrazepam. Both metabolites were produced by the hepatocytes and in the mice model, but the human liver microsomes were only capable of producing minor amounts of the amino metabolite. However, under nitrogen, the amount of amino-meclonazepam produced increased 140 times. This study comprehensively elucidated meclonazepam metabolism and also illustrates that careful selection of in vitro model systems for drug metabolism is needed, always taking into account the expected metabolism of the tested drug.

Place, publisher, year, edition, pages
SPRINGER , 2017. Vol. 19, no 3, 736-742 p.
Keyword [en]
benzodiazepine; in vitro metabolism; LC-MS/MS; new psychoactive substance; toxicokinetics
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:liu:diva-137843DOI: 10.1208/s12248-016-0040-xISI: 000400565300014PubMedID: 28091881OAI: oai:DiVA.org:liu-137843DiVA: diva2:1105159
Available from: 2017-06-02 Created: 2017-06-02 Last updated: 2017-06-02

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Vikingsson, SvanteWohlfarth, ArianeGreen, HenrikJosefsson, MartinKugelberg, FredrikKronstrand, Robert
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