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

Author(s): Taísa Busaranho Franchin, Bruna Cristina Ulian Silva, Rone Aparecido DeGrandis, Michelle Fidelis Corrêa, Cecília Maria Simões de Queiroz Aranha, Joáo Paulo S. Fernandes, Michel Leandro Campos*, Rosângela Gonçalves Peccinini

Journal Name: Current Drug Metabolism

Volume 21 , Issue 9 , 2020

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


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 (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.

Keywords: Pyrazinoic acid, permeability, chemical stability, plasma stability, metabolism, pharmacokinetics.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Page: [714 - 721]
Pages: 8
DOI: 10.2174/1389200221666200907145722
Price: $65

Article Metrics

PDF: 22