Assessment of the physicochemical properties and stability for pharmaco-kinetic prediction of pyrazinoic acid derivatives

dc.contributor.authorFranchin, Taísa Busaranho [UNESP]
dc.contributor.authorSilva, Bruna Cristina Ulian [UNESP]
dc.contributor.authorDegrandis, Rone Aparecido [UNESP]
dc.contributor.authorCorrêa, Michelle Fidelis
dc.contributor.authorAranha, Cecília Maria Simões de Queiroz
dc.contributor.authorFernandes, João Paulo S.
dc.contributor.authorCampos, Michel Leandro
dc.contributor.authorPeccinini, Rosângela Gonçalves [UNESP]
dc.contributor.institutionUniversidade Estadual Paulista (Unesp)
dc.contributor.institutionFederal University of Mato Grosso
dc.contributor.institutionUniversidade de São Paulo (USP)
dc.description.abstractBackground: 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 (Papp) 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 III 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.en
dc.description.affiliationDepartment of Natural Active Principles and Toxicology São Paulo State University (UNESP)
dc.description.affiliationDepartment of Biological Sciences São Paulo State University
dc.description.affiliationHealth Research and Education Center (NU-PADS) Federal University of Mato Grosso
dc.description.affiliationDepartment of Pharmaceutical Sciences Federal University of São Paulo
dc.description.affiliationUnespDepartment of Natural Active Principles and Toxicology São Paulo State University (UNESP)
dc.description.affiliationUnespDepartment of Biological Sciences São Paulo State University
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorshipIdFAPESP: 2016/23229-1
dc.identifier.citationCurrent Drug Metabolism, v. 21, n. 9, p. 714-721, 2020.
dc.relation.ispartofCurrent Drug Metabolism
dc.subjectChemical stability
dc.subjectPlasma stability
dc.subjectPyrazinoic acid
dc.titleAssessment of the physicochemical properties and stability for pharmaco-kinetic prediction of pyrazinoic acid derivativesen