Bemethyl is an actoprotector, an antihypoxant, and a moderate psychostimulant. Even though the therapeutic effectiveness of bemethyl is well documented, there is a gap in knowledge regarding its metabolic products and their quantitative and qualitative characteristics. Since 2018, bemethyl is included to the Monitoring Program of the World Anti-Doping Agency, which highlights the challenge of identifying its urinary metabolites. The objective of the study was to investigate the biotransformation pathways of bemethyl using a combination of liquid chromatography-high-resolution mass spectrometry and in silico studies. Metabolites were analyzed in a 24 h rat urine collected after oral administration of bemethyl at a single dose of 330 mg/kg. The urine samples were prepared for analysis by a procedure developed in the present work and analyzed by high performance liquid chromatography–tandem mass spectrometry. For the first time, nine metabolites of bemethyl with six molecular formulas were identified in rat urine. The most abundant metabolite was a benzimidazole–acetylcysteine conjugate; this biotransformation pathway is associated with the detoxification of xenobiotics. The BioTransformer and GLORY computational tools were used to predict bemethyl metabolites in silico. The molecular docking of bemethyl and its derivatives to the binding site of glutathione S-transferase has revealed the mechanism of bemethyl conjugation with glutathione. The findings will help to understand the pharmacokinetics and pharmacodynamics of actoprotectors and to improve antihypoxant and adaptogenic therapy.
Wipe sampling is widely used for microbiological control purposes. Sanitary and chemical studies also include analysis of samples wiped from the work surfaces during routine and periodic working conditions safety inspections at chemical facilities. The analysis also allows assessing the toxicity and hazard of items/structures that could be in contact with highly toxic substances. This study aimed to investigate the capabilities and limitations of the surface wipe sample analysis method in control of residual contamination of equipment and building structures of a former chemical weapons destruction facilities (CWDF) with sulfur mustard and O-isobutyl-S(2-diethylaminoethyl) methylphosphonothioate (VR), as well as their degradation products. Gas chromatography with tandem mass spectrometry (GC-MS/MS) enabled identification of the sulfur mustard markers, high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS) allowed identifying VR markers. An assessment of the matrix influence on the results of GC-MS/MS and HPLC-MS/MS analysis was carried out. The matrix effect was established to affect the results the most in case of HPLC-MS/MS analysis: for GC-MS/MS analysis of target substances, the matrix factor averaged at 60–80%, for HPLC-MS/ MS it was less than 40%. The average percent sulfur mustard recoveries from three types of surfaces (PVC tiles, laminate and metal plates) was 9 ± 2%, 0.13 ± 0.02% and 0.10 ± 0.03%; in case of VR, the recoveries was 2.7 ± 0.5%, 11.8 ± 0.3% and 0.8 ± 0.1%, respectively. The limits of detection for sulfur mustard by GC-MS/MS and VR by HPLC-MS/MS were established at 0.001 MPL and 0.02 MPL, respectively. The developed approaches were applied to the analysis of wipe samples from the surfaces of the equipment and engineering structures of the former CWDF.
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