Pharmacokinetics and metabolism of brexpiprazole, a novel serotonin-dopamine activity modulator and its main metabolite in rat, monkey and human.
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Sasabe H, Koga T, Furukawa M, Matsunaga M, Kaneko Y, Koyama N, Hirao Y, Akazawa H, Kawabata M, Kashiyama E, Takeuchi K
Pharmacokinetics and metabolism of brexpiprazole, a novel serotonin-dopamine activity modulator and its main metabolite in rat, monkey and human.
Xenobiotica. 2021 May;51(5):590-604. doi: 10.1080/00498254.2021.1890275. Epub 2021 Mar 9.
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- 33685346 [ View in PubMed]
- 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 V(d,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 D(2) 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.
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