Assessment of the Physicochemical Properties and Stability for Pharmacokinetic Prediction of Pyrazinoic Acid Derivatives

Autor(es)

Franchin, Taisa Busaranho ^[1] ; Ulian Silva, Bruna Cristina ^[1] ; DeGrandis, Rone Aparecido ^[2] ; Correa, Michelle Fidelis ^[3] ; Simoes de Queiroz Aranha, Cecilia Maria ^[3] ; Fernandes, Joao Paulo S. ^[3] ; Campos, Michel Leandro ^[4] ; Peccinini, Rosangela Goncalves ^[1]

Afiliação do(s) autor(es)

^[1] Sao Paulo State Univ UNESP, Dept Nat Act Principles & Toxicol, Araraquara, SP - Brazil

^[2] Sao Paulo State Univ, Dept Biol Sci, Araraquara, SP - Brazil

^[3] Univ Fed Sao Paulo, Dept Pharmaceut Sci, Diadema, SP - Brazil

^[4] Univ Fed Mato Grosso, Hlth Res & Educ Ctr NUPADS, 1200 Alexandre Ferronato Ave, BR-78550728 Sinop, MT - Brazil

• Tipo de documento: Artigo Científico
• Fonte: CURRENT DRUG METABOLISM; v. 21, n. 9, p. 714-721, 2020.
• Citações Web of Science: 0

Resumo

Background: Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis, which still has high prevalence worldwide. in addition, cases of drug resistance are frequently observed. In the search for new anti-TB drugs, compounds with antimycobacterial activity have been developed, such as derivatives of pyrazinoic acid, which is the main pyrazinamide metabolite. In a previous study, the compounds were evaluated and showed moderate antimycobacterial activity and no important cytotoxic profile; however, information about their pharmacokinetic profile is lacking. Objective: The aim of this work was to perform physicochemical, permeability, and metabolic properties of four pyrazinoic acid esters. Method: The compounds were analyzed for their chemical stability, n-octanol:water partition coefficient (logP) and apparent permeability (P-app) in monolayer of Caco-2 cells. The stability of the compounds in rat and human microsomes and in rat plasma was also evaluated. Results: The compounds I. II and IV were found to be hydrophilic, while compound Ill was the most lipophilic (logP 1.59) compound. All compounds showed stability at the three evaluated pHs (1.2, 7.4 and 8.8). The apparent permeability measured suggests good intestinal absorption of the compounds. Additionally, the compounds showed metabolic stability under action of human and rat microsomal enzymes and stability in rat plasma for at least 6 hours. Conclusion: The results bring favorable perspectives for the future development of the evaluated compounds and other pyrazinoic acid derivatives. (AU)

• Processo FAPESP: 16/23139-2 - Síntese e avaliação biológica de compostos da série LINS01 como agentes pró-cognitivos: uma abordagem multialvo
• Beneficiário: Michelle Fidelis Corrêa
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 16/25028-3 - Anti-histamínicos H3R/H4R como agentes pró-cognitivos: uma abordagem multialvo
• Beneficiário: João Paulo dos Santos Fernandes
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 16/23229-1 - Estudo de ADME de candidatos a fármacos para o tratamento da tuberculose
• Beneficiário: Taísa Busaranho Franchin
• Modalidade de apoio: Bolsas no Brasil - Mestrado