Detection and identification of the designer benzodiazepine flubromazepam and preliminary data on its metabolism and pharmacokinetics

Abstract

The appearance of pyrazolam in Internet shops selling 'research chemicals' in 2012 marked the beginning of designer benzodiazepines being sold as recreational drugs or 'self medication'. With recent changes in national narcotics laws in many countries, where two uncontrolled benzodiazepines (phenazepam and etizolam), which were marketed by pharmaceutical companies in some countries, were scheduled, clandestine laboratories seem to turn to poorly characterized research drug candidates as legal substitutes. Following the appearance of pyrazolam, it comes with no surprise that recently, flubromazepam (7-bromo-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one), a second designer benzodiazepine, was offered on the market. In this article, this new compound was characterized using nuclear magnetic resonance, gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS/MS) and liquid chromatography quadrupole time-of-flight MS (LC-Q-ToF-MS). Additionally, a study was carried out, in which one of the authors consumed 4 mg of flubromazepam to gain preliminary data on the pharmacokinetic properties and the metabolism of this compound. For this purpose, serum as well as urine samples were collected for up to 31 days post-ingestion and analyzed applying LC-MS/MS and LC-Q-ToF-MS techniques. On the basis of this study, flubromazepam appears to have an extremely long elimination half-life of more than 100 h. One monohydroxylated compound and the debrominated compound could be identified as the predominant metabolites, the first allowing a detection of a consumption for up to 28 days post-ingestion when analyzing urine samples in our case. Additionally, various immunochemical assays were evaluated, showing that the cross-reactivity of the used assay seems not to be sufficient for safe detection of the applied dose in urine samples, bearing the risk that it could be misused in drug-withdrawal settings or in other circumstances requiring regular drug testing. Furthermore, it may be used in drug-facilitated crimes without being detected.

In vitro studies on flubromazolam metabolism and detection of its metabolites in authentic forensic samples

“…[3] Flubromazolam (8-bromo-6-(2-fluorophenyl)-1-methyl-H- [1,2,4]triazolo- [4,3a][1,4]benzodiazepine; Fig. 1) is the triazole analogue of flubromazepam, [4] and it is structurally related to triazole benzodiazepines such as alprazolam and triazolam.…”

Novel psychoactive substances: types, mechanisms of action, and effects

“…10 Acutely, NPS benzodiazepines have similar clinical effects to established compounds such as diazepam, with sedative, anxiolytic, hypnotic, and anticonvulsant properties. Some users of NPS benzodiazepines report that they have much longer durations of actions and effects than established agents, and several compounds have long half lives (flubromazepam, for example, having a half life of 100 hours 63 ). While this reduces dependency potential, unwanted effects can persist for a long time and there are greater risks of accidental overdose.…”

An overview of emerging and new psychoactive substances in the United Kingdom

“…Research into the pharmacokinetics and pharmacodynamics of flubromazepam is pretty scarce with only one study found on Pubmed at the time this review where one of the authors actually ingested 4mg of the drug to obtain data [103]. Flubromazepam has been reported as having a half-life of more than 106 hours with metabolites detectable by LC-MS/MS for up to 28 days after consumption.…”

“…Flubromazepam (26) is the second of the class to be put on the market and was a drug candidate described first in 1962 by Sternbach et al Its potency is said to be possibly higher than those of bromazepam, diazepam and nitrazepam [102,103].…”

“…Flubromazepam has been reported as having a half-life of more than 106 hours with metabolites detectable by LC-MS/MS for up to 28 days after consumption. However, detection of the drug with immunochemical assays were difficult and may indicate the potential use of flubromazepam in drug-facilitated crimes or in situations where drug-testing is performed [103].…”