title: Disposition of TAK-044, a new endothelin antagonist, in rats and dogs.
abstract: The disposition of TAK-044 (cyclo[D-alpha-aspartyl-3-[(4-phenylpiperazin-1-yl)carbonyl]-L-alanyl-L- alpha-aspartyl-D-2-(2-thienyl) glycyl-L-leucyl-D-tryptophyl] disodium, CAS 157380-72-8), a new endothelin antagonist, was studied in rats and dogs by using 14C-labeled drug ([14C]TAK-044). After a single intravenous administration of [14C]TAK-044 at 3 mg/kg to rats and dogs, the concentrations of TAK-044 in plasma declined biphasically; t1/2 alpha and t1/2 beta were 0.03 and 1.10 h in rats, and 0.06 and 0.57 h in dogs, respectively. Plasma clearance and the volume of distribution at steady-state for TAK-044 were 1.66 l/h/kg and 2.09 l/kg in rats, 2.37 l/h/kg and 0.50 l/kg in dogs, respectively. In rats, TAK-044 was distributed widely into tissues, but the 14C concentrations in tissues except for the liver, kidney, and intestine were lower than that in plasma. The in vitro protein binding amounted to 91 to 92% in rat plasma and 88 to 90% in dog plasma. TAK-044 was hardly distributed into the erythrocytes of either species. TAK-044 was hardly metabolized, the radioactivity in plasma and excreta being mostly unchanged compound. Elimination of the radioactivity from the body was almost completed within 48 h in either species. The dosed radioactivity was excreted mostly in the feces via the hepatobiliary route. The rate of excretion of TAK-044 in the bile was dose-dependently prolonged.
authors.affiliation: Drug Analysis and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan. Maeshiba_Yoshihiro@takeda.co.jp
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Maeshiba
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takeuchi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kondo
authors.forename: Kenji
authors.initials: K
authors.lastname: Yamashita
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Tsukuda
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Yoshimura
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D001798:Blood Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D004285:Dogs; D016232:Endothelins / Q000037:antagonists & inhibitors*; D004912:Erythrocytes / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D006207:Half-Life; D008297:Male; D010456:Peptides, Cyclic / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
chemical_list: D001798:Blood Proteins; D016232:Endothelins; D010456:Peptides, Cyclic; C088196:TAK 044