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In vitro drug metabolism and pharmacokinetics of a novel thiazolidinedione derivative, a potential anticancer compound
Published in Elsevier BV
PMID: 31787460
Volume: 179

Thiazolidinediones are known for their activity against Type 2 diabetes and are currently being repurposed for their potent anti-cancer activity. In the present study, we have assessed in vitro metabolic properties and in vivo pharmacokinetic parameters of a novel thiazolidinedione derivative, BIT-15-67, a potential anticancer compound. BIT-15-67 showed low solubility in aqueous buffers at different pH values. The permeability was determined across the Caco-2 monolayer and BIT-15-67 showed high permeability and an efflux ratio of less than 2 suggesting that it is not a substrate of the efflux transporters (P-gp & BCRP). The plasma protein binding was evaluated by equilibrium dialysis and the compound exhibited moderate binding to mouse and rat plasma proteins. BIT-15-67 was stable (half-life > 30 min.) in mouse, rat, dog and human liver microsomes and unstable (half-life <15 min.) in rat hepatocytes suggesting possible Phase II metabolism. Liquid chromatography-tandem mass spectrometry was used to identify Phase I and Phase II metabolites. One of each Phase I and Phase II metabolites have been identified in rat hepatocytes samples. The BIT-15-67 is not an inhibitor of CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. The PK parameters were determined in both male and female Wistar rats after single intravenous dose administration of BIT-15-67. In rats, the mean plasma clearance of BIT-15-67 was higher in males than in females and the terminal plasma elimination half-life was shorter in males than in females. The compound was highly distributed in the tissues. Overall, the absolute oral bioavailability was 5-fold higher in females (38 %) than in males (7 %). In female nude mice with tumors, BIT-15-67 was well distributed among the collected tissues with the highest concentration in the liver. The ratio of the concentrations in tumor vs. the plasma was 0.5 which could be an important attribute in the development of the compound for anti-cancer research. © 2019 Elsevier B.V.

About the journal
JournalData powered by TypesetJournal of Pharmaceutical and Biomedical Analysis
PublisherData powered by TypesetElsevier BV
Open Access0