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

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 (t(1/2)) in plasma was observed in animals and a low total body clearance with high distribution volume was consistent with the long t(1/2). 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 t(1/2). 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.