Characterization and in vitro phase I microsomal metabolism of designer benzodiazepines: An update comprising flunitrazolam, norflurazepam, and 4'-chlorodiazepam (Ro5-4864)
Björn Moosmann, Philippe Bisel, Folker Westphal, Maurice Wilde, Jürgen Kempf, Verena Angerer & Volker Auwärter
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abstract
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The number of newly appearing benzodiazepine derivatives on the new
psychoactive substances (NPS) drug market has increased over the
last couple of years totaling 23 'designer benzodiazepines'
monitored at the end of 2017 by the European Monitoring Centre for
Drugs and Drug Addiction. In the present study, three
benzodiazepines [flunitrazolam, norflurazepam, and 4'-chlorodiazepam
(Ro5-4864)] 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 gas chromatography-mass spectrometry
(GC-MS), liquid chromatography-tandem mass spectrometry (LC MS/MS),
liquid chromatography-quadrupole time of flight-mass spectrometry
(LC-QTOF-MS) analysis and nuclear magnetic resonance (NMR)
spectroscopy. The metabolic steps of flunitrazolam were
monohydroxylation, dihydroxylation, and reduction of the nitro
function. The detected in vitro phase I metabolites of norflurazepam
were hydroxynorflurazepam and dihydroxynorflurazepam.
4'-Chlorodiazepam biotransformation consisted of N-dealkylation and
hydroxylation. It has to be noted that 4'-chlorodiazepam and its
metabolites show almost identical LC-MS/MS fragmentation patterns to
diclazepam and its metabolites (delorazepam, lormetazepam, and
lorazepam), making a sufficient chromatographic separation
inevitable. Sale of norflurazepam, the metabolite of the prescribed
benzodiazepines flurazepam and fludiazepam, presents the risk of
incorrect interpretation of analytical findings.
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citation
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Moosmann B, Bisel P, Westphal F, Wilde M, Kempf J, Angerer V,
Auwärter V. Characterization and in vitro phase I microsomal
metabolism of designer benzodiazepines: An update comprising
flunitrazolam, norflurazepam, and 4'-chlorodiazepam (Ro5-4864). Drug
Test Anal 2019; 11:541-549.
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type
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journal paper/review (English)
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date of publishing
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05-02-2019
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journal title
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Drug Test Anal (11/3)
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ISSN electronic
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1942-7611
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pages
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541-549
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PubMed
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30578721
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DOI
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10.1002/dta.2561
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