Abstract
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.
Highlights
Introduction published maps and institutional affilThe benzimidazole core is present in a large number of drugs with a broad spectrum of biological activity [1]
We reported the chemical formulas of six compounds that were obtained by the examining of urine samples of rats treated with bemethyl and suggested that these compounds could be considered as possible bemethyl metabolites [9]
With all the great potential of LC–MS/HRMS to identify xenobiotic metabolites in multicomponent biomatrices, the xenobiotic biotransformation pathways are impossible to establish without additional information
Summary
Introduction published maps and institutional affilThe benzimidazole core is present in a large number of drugs with a broad spectrum of biological activity [1]. The mechanism of action of bemethyl involves the activation of the cell genome and a positive modulating effect on protein synthesis in the body [2]. It causes a rapidly developing enhancement of ribonucleic acid (RNA) and protein synthesis in different organs and tissues. Bemethyl is used as an anti-asthenic agent in the therapy of neuroses, organic brain lesions of the traumatic and infectious genesis with the prevalence of asthenic symptoms, and myopathies. It is used in the case of iations
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