Toxicological assessment of SGLT2 inhibitors metabolites using in silico approach

Abstract Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are the latest class of drugs approved to treat type 2 DM (T2DM). Although adverse effects are often caused by a metabolite rather than the drug itself, only the safety assessment of disproportionate drug metabolites is usually performed, w...

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Published in:	Anais da Academia Brasileira de Ciências Vol. 94; no. suppl 3
Main Authors:	JESUS, JÉSSICA B. DE, CONCEIÇÃO, RAISSA A. DA, MACHADO, THAYNÁ R., BARBOSA, MARIA L.C., DOMINGOS, THAISA F.S., CABRAL, LUCIO M., RODRIGUES, CARLOS R., ABRAHIM-VIEIRA, BÁRBARA, SOUZA, ALESSANDRA M.T. DE
Format:	Journal Article
Language:	English
Published:	Academia Brasileira de Ciências 01-01-2022
Subjects:	diabetes in silico toxicology metabolism MULTIDISCIPLINARY SCIENCES SGLT2 inhibitors SGLT2i metabolites SGLT2i metabolites metabolism diabetes in silico toxicology SGLT2 inhibitors
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Summary:	Abstract Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are the latest class of drugs approved to treat type 2 DM (T2DM). Although adverse effects are often caused by a metabolite rather than the drug itself, only the safety assessment of disproportionate drug metabolites is usually performed, which is of particular concern for drugs of chronic use, such as SGLT2i. Bearing this in mind, in silico tools are efficient strategies to reveal the risk assessment of metabolites, being endorsed by many regulatory agencies. Thereby, the goal of this study was to apply in silico methods to provide the metabolites toxicity assessment of the SGLT2i. Toxicological assessment from SGLT2i metabolites retrieved from the literature was estimated using the structure and/or statistical-based alert implemented in DataWarrior and ADMET predictorTM softwares. The drugs and their metabolites displayed no mutagenic, tumorigenic or cardiotoxic risks. Still, M1-2 and M3-1 were recognized as potential hepatotoxic compounds and M1-2, M1-3, M3-1, M3-2, M3-3 and M4-3, were estimated to have very toxic LD50 values in rats. All SGLT2i and the metabolites M3-4, M4-1 and M4-2, were predicted to have reproductive toxicity. These results support the awareness that metabolites may be potential mediators of drug-induced toxicities of the therapeutic agents.
ISSN:	0001-3765 1678-2690 1678-2690
DOI:	10.1590/0001-3765202220211287