Early ADME and Preliminary Toxicity Studies of I-152, an N-Acetyl-l-Cysteine/S-Acetylcysteamine Conjugate

This study aimed to estimate the ADME properties and safety of I-152, a conjugate of N-acetyl-l-cysteine (NAC) and S-acetylcysteamine (also known as S-acetyl-β-mercaptoethylamine; SMEA), linked by an amide bond. Its potent antioxidant and pro-glutathione effects make it of interest for a range of conditions linked to oxidative stress, such as infectious diseases and inflammation. I-152 was characterized in vitro for its stability in plasma, liver microsomes, and hepatocytes; its protein binding; and its AB BA (apical-to-basolateral and basolateral-to-apical) permeability using Caco-2 cells. Derisking and preliminary safety pharmacology assays were performed through a human ether-à-go-go-related gene assay (hERG) and in vitro cellular toxicity tests. The results demonstrated that I-152 is hydrolyzed in human plasma (half-life of about 9 min), human liver microsomes, and hepatocytes, as well as in rat liver microsomes and hepatocytes. In addition, I-152 was found to be permeable across the Caco-2 monolayer, indicating good intestinal absorption. Furthermore, I-152 did not produce detectable toxic effects at concentrations up to 1 mM in vitro assays using human keratinocytes, alveolar epithelial cells, and immortalized human embryonic kidney cells (HEK293T). These findings support further preclinical evaluation as a potential redox-modulating agent and thiol-based approach for viral infections and other conditions associated with oxidative stress.