Preclinical toxicity of innovative molecules: In vitro, in vivo and metabolism prediction
| Autor: | Carlos Alberto Tagliati, D.R. Tonholo, L.C.R. Souza, Thales Kronenberger, Iara Rinco Silva, Vinícius Gonçalves Maltarollo, Renata B. Oliveira, P.O. Azevedo |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Neutral red In silico Drug Evaluation Preclinical Pharmacology Toxicology Cell Line 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine In vivo Cell Line Tumor Toxicity Tests Acute Animals Humans Cytotoxicity Cytotoxins In vitro toxicology Biological activity General Medicine 3T3 Cells Hep G2 Cells Acute toxicity 030104 developmental biology chemistry A549 Cells Neutral Red 030220 oncology & carcinogenesis Toxicity Models Animal Female |
| Zdroj: | Chemico-biological interactions. 315 |
| ISSN: | 1872-7786 |
| Popis: | The lack of predictivity of animal's models has increased the failure rate of drug candidates. Thus, the reversion of this scenario using preliminary in vitro assays and metabolism prediction can reduce the unnecessary use of animals, as well as predict toxic effects at preclinical and clinical stages. The present study aimed to evaluate safety of four biologically active molecules (RN104, RI78, ICH, PCH) with potential therapeutic applications synthesized in our laboratory. Initially, we used MTT cytotoxicity against A549, H9C2, HepG2, LLC-PK1 and NEURO-2 cell lines. RN104 showed the lowest cytotoxicity and further studies were conducted with it. The neutral red (NR) test was performed according to OECD-129 and then acute toxicity test (OECD-423). According to NR results we administered at 300 mg/kg on animals; however, no toxic effect was observed, while 2,000 mg/kg resulted in the death of one animal per group. After, metabolism prediction studies, performed using both ligand-based and structure-based, suggests three potential metabolites. In silico results suggested that potential metabolites could be fast eliminated and, then, this could be an explanation for lower observed toxicity in in vivo experiments. The results showed limitations of the NR as a predictor of the initial dose for the acute toxicity study, which may be related to metabolism. Therefore, the combination of theoretical and experimental studies is relevant to a general understanding of new molecule's toxicity. |
| Databáze: | OpenAIRE |
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