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, 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 predictor TM 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 LD 50 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 druginduced toxicities of the therapeutic agents.

Metabolism and Chemical Degradation of New Antidiabetic Drugs: A Review of Analytical Approaches for Analysis of Glutides and Gliflozins

“…However, their amounts were almost too low to quantify them using the above method [ 29 ]. In the study of De Jesus et al [ 40 ], the above-mentioned structures for the mentioned CANA metabolites were confirmed.…”

“…These SGLT2 inhibitors that metabolize through glucuronidation can be subsequently eliminated with urine. Such an excretion process can be facilitated by organic anion transporters, which are responsible for the uptake of various organic anionic compounds such as glucuronidation and sulfation drug metabolites [ 40 ].…”

“…These SGLT2 inhibitors that metabolize through glucuronidation can be subsequently eliminated with urine. Such an excretion process can be facilitated by organic anion transporters, which are responsible for the uptake of various organic anionic compounds such as glucuronidation and sulfation drug metabolites [40]. Furthermore, the more or less important metabolic pathway of SGLT2 inhibitors via oxidative reactions occurred, e.g., for BEXA, DAPA, ERTU, LUSE, and TOFO.…”

“…However, their amounts were almost too low to quantify them using the above method [29]. In the study of De Jesus et al [40], the above-mentioned structures for the mentioned CANA metabolites were confirmed. In addition, LC-MS experiments were performed to study DAPA metabolism (Table 1), and a few products of metabolism were proposed, i.e., DAPA-M1-DAPA-M3 (Figure 5) [31].…”