Journal
FRONTIERS IN PHARMACOLOGY
Volume 13, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2022.1001308
Keywords
pharmacokinetics; bioavailability; glytrexate; plasma protein binding; antifolate
Categories
Funding
- National Natural Science Foundation of China
- S&T Program of Hebei [82073681]
- Hebei Natural Science Foundation [19274801D, 20374801D]
- [H2020206584]
- [H2021206088]
- [H2020206067]
- [H2022206327]
Ask authors/readers for more resources
Glytrexate, a novel multitarget folate antagonist developed by our team, shows inhibitory effects on various cancer cell types, especially KB tumor cells. A liquid chromatography-tandem mass spectrometry method was developed and applied to evaluate the stability, plasma protein binding, and pharmacokinetics of glytrexate. Results suggest that glytrexate has potential clinical application prospects as an injection formulation compared to oral administration.
Glytrexate, developed by our team, as a novel multitarget folate antagonist, has inhibitory effects on a variety of cancer cell types, especially KB tumor cells (IC50 0.078 nM), and thus has antitumor drug development prospects. However, its pharmacokinetics and plasma protein binding properties remain unknown. In this study a selective and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and verified to facilitate biological analysis. The bioanalysis method was applied to evaluate the stability, plasma protein binding, and pharmacokinetics of glytrexate. Glytrexate is more stable in human plasma than in rat plasma and in human liver microsomes. The binding of glytrexate to human plasma proteins was higher than that to rat plasma proteins, both of which were less than 30%, suggesting that glytrexate may be at a higher concentration at the pharmacologic target receptor(s) in tissues. Pharmacokinetic characteristics were determined by noncompartmental analysis after administration of single oral (12.5, 25 and 50 mg/kg) and intravenous (2 mg/kg) doses in rats. According to the rat oral pharmacokinetic characteristics, glytrexate had linear dynamics in a dose range of 12.5-50 mg/kg and a poor oral bioavailability of 0.57-1.15%. The investigation revealed that the intravenous half-life, AUC, and C-max of glytrexate were higher than those of pemetrexed. Pemetrexed is generally produced as an injection preparation. This provides ideas for the development of glytrexate formulations. Therefore, glytrexate injection has clinical application prospects compared to oral administration. This study provides a basis for further investigations into the pharmacological effects and clinical uses of glytrexate.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available