In vivo toxicity, metabolism and pharmacokinetic properties of FAK inhibitor 14 or Y15 (1, 2, 4, 5-benzenetetramine tetrahydrochloride).

Abstract

Y15 or inhibitor 14 (1,2,4,5-benzenetetramine tetrahydrochloride) is a potent and specific inhibitor of focal adhesion kinase that inhibits its autophosphorylation activity, decreases the viability of cancer cells, and blocks tumor growth. In this preclinical study, we analyzed the pharmacokinetics of Y15 in mice plasma, its metabolic stability in mouse and human liver microsomes and toxicity in mice. The pharmacokinetics study in mice demonstrated that, following intraperitoneal administration at 30mg/kg dose, Y15 was very rapidly absorbed in mice, reaching maximum plasma concentration in 4.8min. Y15 rapidly metabolized in mouse and human liver microsomes with half-life t1/2 of 6.9 and 11.6min, respectively. The maximal tolerated dose of single-dose administration of Y15 by oral administration was 200mg/kg, and the multiple maximum tolerated dose of Y15 was 100mg/kg by PO during 7day study. Y15 did not cause any mortality or statistically significant differences in the body weight at 30mg/kg by IP during 28-day study, and at 100mg/kg by PO during the 7-day study. There were no clinical chemical, hematological, or histopathological changes in different mice organs at 30mg/kg by IP during 28days and at 100mg/kg dose by PO during 7days. Thus, this is the first preclinical toxicity, pharmacokinetics, and metabolic stability study of Y15 inhibitor. Further development of Y15 will provide a basis for new therapeutic and future clinical studies.