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| Author(s): |
Taísa Busaranho Franchin
Total Authors: 1
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| Document type: | Master's Dissertation |
| Press: | Araraquara. 2019-03-21. |
| Institution: | Universidade Estadual Paulista (Unesp). Faculdade de Ciências Farmacêuticas. Araraquara |
| Defense date: | 2019-02-22 |
| Advisor: | Rosangela Goncalves Peccinini; Michel Leandro de Campos |
| Abstract | |
Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis which, although recognized for many years, still occurs frequently in society, as well as cases of drug resistance, which has shown a significant increase in recent years. In the search for new treatment strategies, researchers at Unifesp-Diadema have developed new compounds with potential antimycobacterial activity called methyl pyrazinoate (I), ethyl pyrazinoate (II), butyl pyrazinoate (III) and 2- (pyrazine-2 -carbonyloxy) ethyl] pyrazine-2-carboxylate (IV), derivatives of pyrazinoic acid, pyrazinamide's main metabolite. In vitro assays such as the evaluation of physicochemical properties and assays that evaluate absorption, distribution, metabolism and excretion (ADME), aid in the prediction of pharmacokinetic characteristics at an early stage of development, allowing the selection of the best candidates for new drugs. The objective of the present study was the physical-chemical screening (determination of partition coefficient and chemical stability at pHs of 1.2, 7.4 and 8.8) and ADME tests (calculation of the apparent permeability in monolayer of Caco-2 cells, evaluation of metabolic stability in rat and human microsomes and evaluation of stability in rat plasma). The compounds presented logP negative value, indicating hydrophilicity and stability was observed the three pHs evaluated. The apparent permeability calculated for compounds I, II, III and IV resulted in values of 4.66 x10-6; 4.14 x10-6; 66 x10-6 and 1.61x10-6 cm/s, these values indicate a good expectation of absorption, especially for III, whose result brings expectations of complete absorption. The compounds showed metabolic stability front human and rat microsomal enzymes. Compounds I and IV showed instability in rat plasma at 8 hours, and compounds II and III at 6 hours. Considering the prolonged time for the occurrence of significant degradation, there is no expectation that this instability will compromise the in vivo action of the compounds. The results bring favorable expectations for the continuity of the development of the evaluated molecules, besides serving as a basis for interpretation and planning of future in vivo assays. (AU) | |
| FAPESP's process: | 16/23229-1 - ADME study of drug candidates for the treatment of tuberculosis |
| Grantee: | Taísa Busaranho Franchin |
| Support Opportunities: | Scholarships in Brazil - Master |