Abstract
BackgroundThe presence of impurities in some drugs may compromise the safety and efficacy of the patient’s treatment. Therefore, establishing of the biological safety of the impurities is essential. Diabetic patients are predisposed to tissue damage due to an increased oxidative stress process; and drug impurities may contribute to these toxic effects. In this context, the aim of this work was to study the toxicity, in 3 T3 cells, of the antidiabetic agents sitagliptin, vildagliptin, and their two main impurities of synthesis (S1 and S2; V1 and V2, respectively).MethodsMTT reduction and neutral red uptake assays were performed in cytotoxicity tests. In addition, DNA damage (measured by comet assay), intracellular free radicals (by DCF), NO production, and mitochondrial membrane potential (ΔψM) were evaluated.ResultsCytotoxicity was observed for impurity V2. Free radicals generation was found at 1000 μM of sitagliptin and 10 μM of both vildagliptin impurities (V1 and V2). A decrease in NO production was observed for all vildagliptin concentrations. No alterations were observed in ΔψM or DNA damage at the tested concentrations.ConclusionsThis study demonstrated that the presence of impurities might increase the cytotoxicity and oxidative stress of the pharmaceutical formulations at the concentrations studied.
Highlights
The presence of impurities in some drugs may compromise the safety and efficacy of the patient’s treatment
Cell culture The 3 T3 cell line was routinely cultured in 75 cm2 flasks (Kasvi, São José dos Pinhais, PR, Brazil) using DMEM supplemented with 10% heat inactivated fetal bovine serum (FBS), 100 U mL− 1 penicillin (Gibco, Paisley, UK), and 100 mg mL− 1 streptomycin (Gibco, Paisley, UK)
Sitagliptin and vildagliptin are used for the treatment of diabetes mellitus
Summary
The presence of impurities in some drugs may compromise the safety and efficacy of the patient’s treatment. Diabetic patients are predisposed to tissue damage due to an increased oxidative stress process; and drug impurities may contribute to these toxic effects. In this context, the aim of this work was to study the toxicity, in 3 T3 cells, of the antidiabetic agents sitagliptin, vildagliptin, and their two main impurities of synthesis (S1 and S2; V1 and V2, respectively). According to ICH-Q3A (R2), there are reporting, Giordani et al BMC Pharmacology and Toxicology 2019, 20(Suppl 1): identification, and qualification thresholds The latter relates to the data acquisition and evaluation process that determines the biological safety of an impurity or a profile of impurities at a safe level [13]. The thresholds for qualification of impurities are based on individual drugs, evidence of the presence of such impurities is important when they are related with adverse reactions in patients [11]
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