Laboratório de Controle de Qualidade Farmacêutico, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.
Laboratório de Toxicologia (LATOX), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.
BMC Pharmacol Toxicol. 2019 Dec 19;20(Suppl 1):82. doi: 10.1186/s40360-019-0354-2.
The 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).
MTT 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.
Cytotoxicity 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.
This study demonstrated that the presence of impurities might increase the cytotoxicity and oxidative stress of the pharmaceutical formulations at the concentrations studied.
一些药物中存在杂质可能会影响患者治疗的安全性和疗效。因此，建立杂质的生物学安全性是至关重要的。糖尿病患者由于氧化应激过程增加而易发生组织损伤；而药物杂质可能会促成这些毒性作用。在这种情况下，本研究的目的是研究抗糖尿病药物西他列汀、维格列汀及其两种主要合成杂质（S1 和 S2；V1 和 V2）在 3T3 细胞中的毒性。
在细胞毒性试验中进行 MTT 还原和中性红摄取测定。此外，还评估了 DNA 损伤（彗星试验测定）、细胞内自由基（DCF 测定）、NO 产生和线粒体膜电位（ΔψM）。
观察到杂质 V2 具有细胞毒性。在 1000μM 的西他列汀和 10μM 的两种维格列汀杂质（V1 和 V2）中发现自由基生成。所有维格列汀浓度下，NO 产生减少。在测试浓度下，ΔψM 或 DNA 损伤没有观察到改变。
本研究表明，杂质的存在可能会增加药物制剂在研究浓度下的细胞毒性和氧化应激。
