title: Pharmacokinetic characterization of the novel TAZ modulator TM-25659 using a multicompartment kinetic model in rats and a possibility of its drug-drug interactions in humans.
abstract: This study evaluated the pharmacokinetics of the novel TAZ modulator TM-25659 in rats following intravenous and oral administration at dose ranges of 0.5-5 mg/kg and 2-10 mg/kg, respectively. Plasma protein binding, plasma stability, liver microsomal stability, CYP inhibition, and transport in Caco-2 cells were also evaluated. After intravenous injection, systemic clearance, steady-state volumes of distribution, and half-life were dose-independent, with values ranging from 0.434-0.890 mL · h(-1) · kg(-1), 2.02-4.22 mL/kg, and 4.60-7.40 h, respectively. Mean absolute oral bioavailability was 50.9% and was not dose dependent. Recovery of TM-25659 was 43.6% in bile and <1% in urine. In pharmacokinetic modeling studies, the three-compartment (3C) model was appropriate for understanding these parameters in rats. TM-25659 was stable in plasma. Plasma protein binding was approximately 99.2%, and was concentration-independent. TM-25659 showed high permeation of Caco-2 cells and did not appear to inhibit CYP450. TM-25659 was metabolized in phase I and II steps in rat liver microsomes. In conclusion, the pharmacokinetics of TM-25659 was characterized for intravenous and oral administration at doses of 0.5-5 and 2-10 mg/kg, respectively. TM-25659 was eliminated primarily by hepatic metabolism and urinary excretion.
authors.affiliation: Drug Discovery Platform Technology Team, Medicinal Science Division, Korea Research Institute of Chemical Technology, Daejeon, South Korea.
authors.forename: Kyeong-Ryoon
authors.initials: KR
authors.lastname: Lee
authors.forename: Sung Heum
authors.initials: SH
authors.lastname: Choi
authors.forename: Jin-Sook
authors.initials: JS
authors.lastname: Song
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Kwak
authors.forename: Yoon-Jee
authors.initials: YJ
authors.lastname: Chae
authors.forename: So Hee
authors.initials: SH
authors.lastname: Im
authors.forename: Byung Hoi
authors.initials: BH
authors.lastname: Lee
authors.forename: Hyewon
authors.initials: H
authors.lastname: Seo
authors.forename: Woon-Ki
authors.initials: WK
authors.lastname: Cho
authors.forename: Min-Sun
authors.initials: MS
authors.lastname: Kim
authors.forename: Nak Jeong
authors.initials: NJ
authors.lastname: Kim
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Ahn
authors.forename: Myung Ae
authors.initials: MA
authors.lastname: Bae
mesh_terms: D000284:Administration, Oral; D000465:Algorithms; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D018938:Caco-2 Cells; D065607:Cytochrome P-450 Enzyme Inhibitors; D004347:Drug Interactions; D006801:Humans; D007275:Injections, Intravenous; D047908:Intracellular Signaling Peptides and Proteins / Q000187:drug effects; D007700:Kinetics; D008297:Male; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins
chemical_list: C572937:2-butyl-5-methyl-6-(pyridine-3-yl)-3-(2'-(1H-tetrazole-5-yl)-biphenyl-4-ylmethyl)-3H-imidazo(4,5-b)pyridine; D001798:Blood Proteins; D019086:Bridged Bicyclo Compounds, Heterocyclic; D065607:Cytochrome P-450 Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D013777:Tetrazoles; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human