Pharmacokinetics and metabolism of brexpiprazole, a novel serotonin-dopamine activity modulator and its main metabolite in rat, monkey and human
Year: 2021
Type: article
Abstract: The pharmacokinetics of brexpiprazole were investigated in the in vitro and in vivo.The total body clearance of brexpiprazole in rat and monkey was 2.32 and 0.326 L/h/kg, respectively, after intravenous administration, and oral availability was 13.6% and 31.0%, respectively. Dose-dependent exposures were observed at dose ranges between 1–30 mg/kg in the rat and 0.1–3 mg/kg in the monkey.Brexpiprazole distributed widely to body tissues, and Vd,z were 2.81 and 1.82 L/kg in rat and monkey, respectively. The serum protein binding of brexpiprazole was 99% or more in animals and human. Uniform distribution character among the species was suggested by a traditional animal scale-up method.A common main metabolite, DM-3411 was found in animals and humans in the metabolic reactions with the liver S9 fraction. CYP3A4 and CYP2D6 were predominantly involved in the metabolism.The affinity of DM-3411 for D2 receptors was lower than that of brexpiprazole, and neither DM-3411 nor any metabolites with affinity other than M3 were detected in the brain, demonstrating that brexpiprazole is only involved in the pharmacological effects.Overall, brexpiprazole has a simple pharmacokinetic profile with good metabolic stability, linear kinetics, and no remarkable species differences with regard to metabolism and tissue distribution.
Source: Xenobiotica
Authors: Hiroyuki Sasabe, Toshihisa Koga, Masayuki Furukawa, Masayuki Matsunaga, Yosuke Kaneko, Noriyuki Koyama, Yukihiro Hirao, Hitomi Akazawa, Mitsuhiko Kawabata, Eiji Kashiyama, Kenji Takeuchi
Institutions: Otsuka (Japan), Shin Nippon Biomedical Laboratories (Japan)
Language: English
Subfield: Pharmacology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3135873052