Biopharmaceutic parameters, pharmacokinetics, transport and CYP-mediated drug interactions of IIIM-017: A novel nitroimidazooxazole analogue with anti-tuberculosis activity

摘要

Nitroimidazoles are emerging as a new class of therapeutic agents with potent anti-tubercular activity. CSIR-IIIM has synthesized a novel nitrohydroimidazooxazole (NHIO) analogue, IIIM-017 with a MIC of 0.37 mu g/ml (against H37Rv). Here, we aim at further exploration of physicochemical properties and preclinical absorption, metabolism, disposition and pharmacokinetics of IIIM-017. In this study, in silico physicochemical parameters, lipophilicity, permeability, transport, hepatotoxicity, CYP mediated drug interactions and pharmacokinetics of IIIM-017 were investigated. The results demonstrated that IIIM-017 exhibited good physicochemical properties, comparable to PA-824 and OPC-67683. Caco-2 transport studies revealed that the compound was highly permeable with P-app of 8.85 x 10(-6) (A-B) and 27.69 x 10(-6) (B-A) cm/s. Caco-2 cells were also used to study P-gp mediated transport and inhibition. IIM-017 exhibited very low intrinsic clearance and no substantial hepatotoxicity in vitro. The compound did not have any inhibitory effect on human CYPs 1A2, 2C9, 2D6, 3A4 and 2C19 up to concentration of 30 mu M. In vivo pharmacokinetics was performed on balb/c mice at 5 mg/kg (p.o) and 2.5 mg/kg (i.v.) and plasma drug concentrations were determined by LC-MS/MS. The compound showed satisfactory PK parameters in mice. The results insinuate that IIIM-017 should undergo further development as a potential treatment for tuberculosis.