Title:Assessment of the Physicochemical Properties and Stability for Pharmacokinetic Prediction of Pyrazinoic Acid Derivatives
Volume: 21
Issue: 9
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
Affiliation:
- Health Research and Education Center (NUPADS), Federal University of Mato Grosso, Sinop, Mato Grosso,Brazil
Keywords:
Pyrazinoic acid, permeability, chemical stability, plasma stability, metabolism, pharmacokinetics.
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.
