Acute toxicity and pharmacokinetic parameters of 2-aminopyrrole with antitumour activity

Introduction. One of the most pressing areas of modern pharmacy is the creation of highly effective and safe drugs. The search for antitumor agents, driven by the increasing incidence of cancer, is focused on obtaining targeted drugs. 2-aminopyrrole derivatives synthesised at the Perm State Pharmaceutical Academy have demonstrated high cytostatic activity due to the activation of the mechanism of tumour cell apoptosis in the M phase. Preclinical studies should include toxicometry and determination of the pharmacokinetic parameters of the most active compound, 2-ANPC.

Aim. To study acute toxicity in experiments on mice and rats and the pharmacokinetic parameters of 2-ANPC after a single administration to Wistar line rats.

Materials and methods. The assessment of acute toxicity upon oral administration, with LD₅₀ calculation using Finney's probit analysis method, was conducted in experiments on white non-linear mice and Wistar line rats. The pharmacokinetic parameters of 2-ANPC were studied in male Wistar line rats after administration of the compound per os. A validated method based on high-performance liquid chromatography with tandem mass spectrometry detection (HPLC-MS/MS) was used for the quantitative determination of 2-ANPC in the blood plasma of animals.

Results and discussion. The LD₅₀ of the compound after a single oral administration was determined to be 4434 mg/kg for mice and 1547 mg/kg for rats. The time to reach the maximum concentration of 2-ANPC in rats after a single administration of 150 mg/kg is 2,90 ± 0,32 h, and the half-life of the compound from the body is 4,50 ± 0,49 h. The calculated apparent volume of distribution, which significantly exceeds the anatomical volume, indicates the predominant localisation of the substance in the extravascular space.

Conclusion. The study of acute toxicity in mice established that 2-ANPK belongs to toxicity class 4 (low-toxicity substances) according to the Hodge and Sterner classification and to hazard class 5 of chemical products based on their impact on the body. In an experiment on rats, the pharmacokinetic parameters of 2-ANPC after oral administration were evaluated. The data obtained show the potential for developing an oral dosage form based on this new 2-aminopyrrole derivative with proven antitumor activity.

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