Genotoxic and cytotoxic assessment of sitagliptin and simvastatin alone and in combination.

Type 2 Diabetes Mellitus (T2DM) patients are at high risk of Coronary Heart Disease (CHD) and need a global therapeutic intervention. A fixed-dose combination prescription medication containing anti-diabetic drug (Sitagliptin) and lipid lowering (Simvastatin) has recently been approved. Present study was designed to explore the potential synergistic toxic effects of sitagliptin and simvastatin at cellular level. MTT assay revealed the potential synergistic cytotoxic effect whereas Comet assay spotlighted the genotoxicity. MTT assay conducted on Vero cell lines revealed no significant change in proliferative activity upon treatment with simvastatin but cell survival percentage (CSP) decreased upon treatment with sitagliptin (51% at 1000µg/mL). However, combination of both drugs exhibited a better survival percentage except highest dose combination (1000:500µg/mL) which augmented antiproliferative effects rendering CSP 71.6%. The genotoxic assay spotted that Simvastatin produced less damage to DNA with the threshold of 500µg/ml whereas Sitagliptin significantly damage above the 250µg/mL, However, combination of drugs produced lesser damage than Sitagliptin alone. The findings concluded a non-genotoxic combination of sitagliptin and simvastatin which possess a least cytotoxic potential suggesting the safe use of the combination both in T2DM and CHD.

In vitro toxic evaluation of two gliptins and their main impurities of synthesis.

BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: This study demonstrated that the presence of impurities might increase the cytotoxicity and oxidative stress of the pharmaceutical formulations at the concentrations studied.

Investigation of in vitro genotoxic effects of an anti-diabetic drug sitagliptin.

Sitagliptin is an active ingredient of antidiabetic drug used in the treatment of type 2 diabetes mellitus (T2DM). In this study, the genotoxic effects of sitagliptin were determined in human lymphocytes by using chromosome aberrations (CAs), sister chromatid exchanges (SCEs), micronucleus (MN) and comet assays. 31.25-1000 µg/mL concentrations of sitagliptin were used. Sitagliptin significantly increased the frequency of CAs and SCEs at the highest concentration at 24 h treatment and all concentrations (except 250 µg/mL for CA, except 31.25 and 62.50 µg/mL for SCE) at 48 h treatment compared with solvent control (DMSO). This compound increased the MN at only the highest concentration compared with the solvent control. Mitotic index (MI) significantly decreased at the three highest concentrations of sitagliptin at 48 h treatment. However, replication (RI) and nuclear division (NDI) indices were not affected at all the treatments. Comet assay results indicated that sitagliptin significantly increased mean comet tail intensity and tail moment at only two concentrations (62.50 and 1000 µg/mL for intensity, 125 and 1000 µg/mL for tail moment), and tail length at all concentrations (except 125 and 500 µg/mL). It was concluded that higher concentration of sitagliptin had genotoxic effects in the human lymphocytes in vitro.