Mutagenic and genotoxic in silico QSAR prediction of dimer impurity of gliflozins; canagliflozin, dapaglifozin, and emphagliflozin and in vitro evaluation by Ames and micronucleus test

Abstract

Canagliflozin, Dapagliflozin, and Empagliflozin, glucagon-like peptide-1 receptor agonists, are indicated for managing type II diabetes. Although the genotoxicity profiles of these drugs are well-explored, limited information exists regarding the genotoxic potential of their impurities. In this investigation, the dimer impurities of Canagliflozin, Dapagliflozin, and Empagliflozin underwent both in silico and in vitro assessments for mutagenic potential. Tester strains of Salmonella typhimurium and Escherichia coli were subjected to the Ames test, utilizing concentrations of up to 1 µg per plate, with and without the presence of metabolic activation. Evaluation of micronucleus induction in TK6 cells was conducted through a micronucleus test, exploring concentrations up to 500 µg/mL, with or without the presence of exogenous metabolic activation. Under the specific test conditions, the dimer impurities of Canagliflozin, Dapagliflozin, and Empagliflozin showed no evidence of mutagenicity or clastrogenicity, establishing their in vitro classification as nonmutagenic. These findings align with negative in silico predictions from quantitative structure–activity relationship (QSAR) analyses for mutagenicity and genotoxicity of the dimer impurities. Collectively, these studies contribute clinically relevant safety information by confirming that the dimer impurities of Canagliflozin, Dapagliflozin, and Empagliflozin are nonmutagenic and nongenotoxic, emphasizing the consistency between in silico and in vitro data.

Keywords:

• Canagliflozin
• dapagliflozin
• empagliflozin
• genotoxicity
• mutagenicity
• dimer

Acknowledgement

All author acknowledges Cleanchem Lab for their support in this study.

Authors’ contributions

The study design and data interpretation were undertaken by RR, MS and BTS. In vitro experiments were conducted by BTS, AGP, and MS. RR, AP and BG drafted the article, and AM, RR, AP and DK provided critical revisions before finally approving the version for submission.

Data availability

*The data that support the findings of this study are available on request from the corresponding authors.

Disclosure statement

The authors report no conflict of interest.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.