title: Pharmacokinetics, tissue distribution and identification of putative metabolites of JI-101 - a novel triple kinase inhibitor in rats.
abstract: JI-101, chemically 1-[1-(2-amino-pyridin-4-ylmethyl)-1H-indol-4-yl]-3-(5-bromo-2-methoxy-phenyl)-urea hydrochloride, is a novel orally active kinase inhibitor, which has shown potent in vitro and in vivo anticancer activity against a variety of cancer cell lines and xenografts. It is currently entering Phase II clinical development for the treatment of solid tumors. The aim of the study is to assess the metabolic stability of JI-101 in various pre-clinical and human liver microsomes, to identify the major CYPs (cytochrome β450) involved in the metabolism of JI-101 and identification of putative metabolites. We have also studied the pharmacokinetics, tissue distribution and excretion of JI-101 in Sprague Dawley rats. JI-101 was found to be stable in various liver microsomes tested. JI-101 is highly permeable and not a substrate for P-gp (permeability glycoprotein). JI-101 excreted through bile along with its mono- and di-hydroxy metabolites. Following oral administration, JI-101 was rapidly absorbed, reaching Cmax within 2 h. The t½ of JI-101 with intravenous and oral route was found to be 1.75 ± 0.79 and 2.66 ± 0.13 h, respectively. The Cl and Vd by intravenous route for JI-101 were found to be 13.0 ± 2.62 mL/min/kg and 2.11 ± 1.42 L/kg, respectively. The tissue distribution of JI-101 was extensive with rapid and preferred uptake into lung tissue. Overall, the oral bioavailability of JI-101 is 55% and the primary route of elimination for JI-101 is feces.
authors.affiliation: Drug Metabolism and Pharmacokinetics, Jubilant Biosys, Industrial Suburb, Yeshwanthpur, Bangalore, India.
authors.forename: S D
authors.initials: SD
authors.lastname: Gurav
authors.forename: R R
authors.initials: RR
authors.lastname: Gilibili
authors.forename: S
authors.initials: S
authors.lastname: Jeniffer
authors.forename: Z
authors.initials: Z
authors.lastname: Mohd
authors.forename: S
authors.initials: S
authors.lastname: Giri
authors.forename: R
authors.initials: R
authors.lastname: Govindarajan
authors.forename: N R
authors.initials: NR
authors.lastname: Srinivas
authors.forename: R
authors.initials: R
authors.lastname: Mullangi
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism; D018938:Caco-2 Cells; D002853:Chromatography, Liquid; D019363:Cytochrome P-450 CYP1A1 / Q000502:physiology; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics*; D008297:Male; D010641:Phenotype; D010671:Phenylurea Compounds / Q000493:pharmacokinetics*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D036224:Receptor, EphB4 / Q000037:antagonists & inhibitors*; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution
chemical_list: C561574:1-(1-(2-amino-pyridin-4-ylmethyl)-1H-indol-4-yl)-3-(5-bromo-2-methoxyphenyl)urea; D007211:Indoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D019363:Cytochrome P-450 CYP1A1; D036224:Receptor, EphB4