title: Disposition of the Highly Fat Distributed Compound 1-(4-Methoxyphenyl)-4-(2,2,4,6,7-Pentamethyl -2,3-Dihydro-1-Benzofuran-5-yl)Piperazine (TAK-357) in Rats and Dogs.
abstract: The non-clinical pharmacokinetics (PK) of TAK-357, a highly lipophilic (clogP>6) potential agent for the amelioration of Alzheimer's disease, was investigated in rats and dogs. A long half-life (t1/2) in plasma was observed in animals and a low total body clearance with high distribution volume was consistent with the long t1/2. The absorption, distribution, metabolism and excretion (ADME) studies using radiolabeled TAK-357 revealed that the total radioactivity was highly distributed to the adipose tissues and sustained with high concentration for over 4 weeks after oral administration. The metabolite analysis also revealed that the main component in the plasma and adipose tissues was unchanged TAK-357. The major elimination route of absorbed TAK-357 was suggested to be by metabolism. An ADME study indicated that the adipose tissue is the main depot of remaining TAK-357 in the body and slow release from the adipose tissues contributes to the long t1/2. The PK of highly lipophilic compounds have a tendency to be affected by body weight changes especially changes in the adipose tissues. Therefore, it is considered that the relationship between the plasma levels of TAK-357 and the body weight should be evaluated carefully during the clinical trials.
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Goto
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Moriya
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Mandai
authors.affiliation: Central Nervous System Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Wakabayashi
authors.affiliation: Central Nervous System Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Tsukamoto
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Tagawa
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kondo
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Asahi
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D002250:Carbon Radioisotopes / Q000008:administration & dosage / Q000493:pharmacokinetics; D004285:Dogs; D006207:Half-Life; D007192:Indenes / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D051381:Rats; D014018:Tissue Distribution
chemical_list: D002250:Carbon Radioisotopes; D007192:Indenes; C495910:ramelteon