Pharmacokinetics and metabolism of brexpiprazole, a novel serotonin-dopamine activity modulator and its main metabolite in rat, monkey and human

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.

本研究对布瑞哌唑（brexpiprazole）的药代动力学开展了体外与体内研究。静脉给药后，大鼠与猴体内布瑞哌唑的全身清除率分别为2.32 L/h/kg与0.326 L/h/kg，口服生物利用度分别为13.6%与31.0%。在大鼠1~30 mg/kg、猴0.1~3 mg/kg的给药剂量范围内，均观察到剂量依赖性暴露量变化。布瑞哌唑可广泛分布于机体各组织，大鼠与猴的终末表观分布容积（Vd,z）分别为2.81 L/kg与1.82 L/kg。布瑞哌唑在动物与人体血清中的蛋白结合率均≥99%。采用传统动物种属外推法分析提示，不同种属间布瑞哌唑的分布特征具有一致性。在经肝S9组分介导的代谢反应中，动物与人体均检出共同的主要代谢产物DM-3411，且代谢过程主要由细胞色素P450 3A4（CYP3A4）与细胞色素P450 2D6（CYP2D6）催化。DM-3411对多巴胺D2受体（D2 receptors）的亲和力低于布瑞哌唑，且脑内未检出DM-3411或其他除M3外具有受体亲和力的代谢产物，证实布瑞哌唑是唯一参与药理作用的成分。总体而言，布瑞哌唑具有简洁的药代动力学特征：代谢稳定性良好、药代动力学呈线性，且在代谢与组织分布方面无显著种属差异。