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Characterization and in vitro phase I microsomal metabolism of designer benzodiazepines – an update comprising adinazolam, cloniprazepam, fonazepam, 3‐hydroxyphenazepam, metizolam, and nitrazolam

Designer benzodiazepines represent an emerging class of new psychoactive substances (NPS). While other classes of NPS such as cannabinoid receptor agonists and designer stimulants are mainly consumed for hedonistic reasons, designer benzodiazepines may also be consumed as 'self‐medication' by persons with anxiety or other psychiatric disorders or as stand‐by ‘antidote’ by users of stimulant and hallucinogenic drugs. In the present study, five benzodiazepines (adinazolam, cloniprazepam, fonazepam, 3‐hydroxyphenazepam, and nitrazolam) and one thienodiazepine (metizolam) offered as ‘research chemicals’ on the Internet were characterized and their main in vitro phase I metabolites tentatively identified after incubation with pooled human liver microsomes. For all compounds the structural formula declared by the vendor was confirmed by NMR spectroscopy, GC‐MS, LC MS/MS and LC‐Q‐TOF‐MS analysis. The detected in vitro phase I metabolites of adinazolam were N‐desmethyladinazolam and N‐didesmethyladinazolam. Metizolam showed a similar metabolism to other thienodiazepines comprising of monohydroxylations and dihydroxylation. Cloniprazepam was metabolized to numerous metabolites with the main metabolic steps being N‐dealkylation, hydroxylation and reduction of the nitro function. It has to be noted that clonazepam is a metabolite of cloniprazepam which may lead to difficulties when interpreting analytical findings. Nitrazolam and fonazepam both underwent monohydroxylation and reduction of the nitro function. In the case of 3‐OH‐phenazepam no in vitro phase I metabolites were detected. Formation of licensed benzodiazepines (clonazepam after uptake of cloniprazepam) and the sale of metabolites of prescribed benzodiazepines (fonazepam, identical to norflunitrazepam, and 3‐hydroxyphenazepam) present the risk of incorrect interpretation of analytical findings.

Authors:   Bjoern Moosmann, Philippe Bisel, Florian Franz, Laura M. Huppertz, Volker Auwärter
Journal:   Journal of Mass Spectrometry
Year:   2016
Pages:   n/a
DOI:   10.1002/jms.3840
Publication date:   18-Aug-2016
Facts, background information, dossiers
  • benzodiazepines
  • metabolites
  • metabolism
  • drugs
  • Dihydroxylation
  • anxiety
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