Assessment of the Physicochemical Properties and Stability for Pharmacokinetic Prediction of Pyrazinoic Acid Derivatives.
Pyrazinoic acid
chemical stability
metabolism
permeability
pharmacokinetics
plasma stability
Journal
Current drug metabolism
ISSN: 1875-5453
Titre abrégé: Curr Drug Metab
Pays: Netherlands
ID NLM: 100960533
Informations de publication
Date de publication:
2020
2020
Historique:
received:
17
02
2020
revised:
12
05
2020
accepted:
30
07
2020
pubmed:
9
9
2020
medline:
9
10
2021
entrez:
8
9
2020
Statut:
ppublish
Résumé
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. The aim of this work was to perform physicochemical, permeability, and metabolic properties of four pyrazinoic acid esters. 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. 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. The results bring favorable perspectives for the future development of the evaluated compounds and other pyrazinoic acid derivatives.
Sections du résumé
BACKGROUND
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
OBJECTIVE
The aim of this work was to perform physicochemical, permeability, and metabolic properties of four pyrazinoic acid esters.
METHOD
METHODS
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
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
CONCLUSIONS
The results bring favorable perspectives for the future development of the evaluated compounds and other pyrazinoic acid derivatives.
Identifiants
pubmed: 32895039
pii: CDM-EPUB-109759
doi: 10.2174/1389200221666200907145722
doi:
Substances chimiques
Water
059QF0KO0R
Pyrazinamide
2KNI5N06TI
pyrazinoic acid
2WB23298SP
1-Octanol
NV1779205D
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
714-721Informations de copyright
Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.