Anglia Ruskin Research Online (ARRO)
Browse
Davies_2024.pdf (7.15 MB)

Diclazepam and its metabolites: a chemometric interpretation

Download (7.15 MB)
thesis
posted on 2024-04-08, 15:24 authored by Christopher Davies

Diclazepam is a ‘designer’ benzodiazepine derivative and modified version of the existing pharmaceutically prescribed benzodiazepine diazepam. There is little knowledge regarding its pharmacokinetics, it has never undergone clinical trials, and it was deemed unfit for human consumption in the early 1970s. However, the possible illicit use of diclazepam as both a recreational and a drink spiking drug has recently been reported. Diclazepam metabolises into three pharmaceutically prescribed benzodiazepines (delorazepam, lormetazepam, and lorazepam) with overlapping metabolic pathways, which could make the identification of the parent drug challenging.

The aim of this research was to identify whether delorazepam, lormetazepam, and lorazepam are parent drugs, or whether their detections are due to the metabolism of diclazepam. This was achieved by analysing the metabolite ratios of in vitro metabolised diclazepam, delorazepam, and lormetazepam in pooled human liver microsomes over 240 minutes. Liquid liquid extraction (LLE) was used to extract diclazepam and its metabolites from the incubated microsomes over different incubation times, and analytes detected by a validated gas chromatography-mass spectrometry (GC-MS) method. A calibration model provided limits of detection that ranged between 0.02 to 0.43 μg/ml for diclazepam and its metabolites delorazepam and lormetazepam, and >5 μg/ml for lorazepam, with all precisions below 8.9%.

In vitro metabolism identified possible backward metabolism of diclazepam and its metabolites during incubation. Diclazepam and its metabolite ratios proved that one could differentiate whether the parent drug was diclazepam, or one of its metabolites, thus meeting the aim of this research. In addition, novel chemometric models using principal component analysis showed the potential for differentiating parent benzodiazepines based on their detected metabolite proportions.

The findings from this research could contribute to improving and advancing drug identification and interpretation methods in biological samples. The findings also provides new information for the way in which benzodiazepines may undergo backwards metabolism or chemical conversion to predecessor drugs.

History

Institution

Anglia Ruskin University

File version

  • Published version

Thesis name

  • PhD

Thesis type

  • Doctoral

Thesis submission date

2024-03-12

Legacy Faculty/School/Department

Faculty of Science and Engineering

Usage metrics

    ARU Theses

    Categories

    No categories selected

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC