Preclinical pharmacokinetics and in vitro ADME properties of PAT-1102: a novel HDAC inhibitor for cancer therapy.

Abstract

Background: Histone deacetylases (HDAC) are involved in chromatin remodelling, and histone deacetylases inhibitors have become the interest of research and shown promising antitumor effects against various cancer.

Methods: In the current study, an attempt was made to characterize the preclinical ADME properties of a novel hydroxamic based HDAC inhibitor, PAT-1102, with the help of in vitro assays and in vivo pharmacokinetic experiments in rats.

Results: PAT-1102 showed high aqueous solubility and high Caco-2 permeability in the in vitro assays. It was found to be not a substrate of efflux protein P-gp, found stable in metabolism experiments with incubations of rat and human liver microsomes. Inhibition experiments of human recombinant CYP enzymes revealed that PAT-1102 was not considerably inhibited the major CYP enzymes. PAT-1102 exhibited low plasma protein binding of 58.1% and 54.5% in humans and rats, respectively. In vivo pharmacokinetic studies of PAT-1102 in male and female rats showed bioavailability of 3.7% and 3.0% by oral route, respectively. Previous research findings suggested that PAT-1102 is a potent pan-HDAC inhibitor with good preclinical efficacy.

Conclusion: Considering the overall ADME and pharmacokinetic profile of PAT-1102, as indicated by in vitro and in vivo experiments, the PAT-1102 could be considered as a potential candidate for the advancement of cancer therapy.