Song Yoo-Kyung, Seol Yun-Hwan, Kim Min Ju, Jeong Jong-Woo, Choi Hae-In, Lee Seung-Won, Chae Yoon-Jee, Ahn Sunjoo, Gong Young-Dae, Lee Kyeong-Ryoon, Koo Tae-Sung
Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Ochang-eup 28116, Korea.
Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, Korea.
Pharmaceutics. 2021 Mar 11;13(3):373. doi: 10.3390/pharmaceutics13030373.
Supinoxin is a novel anticancer drug candidate targeting the Y593 phospho-p68 RNA helicase, by exhibiting antiproliferative activity and/or suppression of tumor growth. This study aimed to characterize the in vitro and in vivo pharmacokinetics of supinoxin and attempt physiologically based pharmacokinetic (PBPK) modeling in rats. Supinoxin has good permeability, comparable to that of metoprolol (high permeability compound) in Caco-2 cells, with negligible net absorptive or secretory transport observed. After an intravenous injection at a dose range of 0.5-5 mg/kg, the terminal half-life (i.e., 2.54-2.80 h), systemic clearance (i.e., 691-865 mL/h/kg), and steady state volume of distribution (i.e., 2040-3500 mL/kg) of supinoxin remained unchanged, suggesting dose-independent (i.e., dose-proportional) pharmacokinetics for the dose ranges studied. After oral administration, supinoxin showed modest absorption with an absolute oral bioavailability of 56.9-57.4%. The fecal recovery following intravenous and oral administration was 16.5% and 46.8%, respectively, whereas the urinary recoveries in both administration routes were negligible. Supinoxin was mainly eliminated via NADPH-dependent phase I metabolism (i.e., 58.5% of total clearance), while UDPGA-dependent phase II metabolism appeared negligible in the rat liver microsome. Supinoxin was most abundantly distributed in the adipose tissue, gut, and liver among the nine major tissues studied (i.e., the brain, liver, kidneys, heart, lungs, spleen, gut, muscles, and adipose tissue), and the tissue exposure profiles of supinoxin were well predicted with physiologically based pharmacokinetics.
苏平诺辛是一种新型抗癌候选药物，通过表现出抗增殖活性和/或抑制肿瘤生长来靶向Y593磷酸化-p68 RNA解旋酶。本研究旨在表征苏平诺辛的体外和体内药代动力学，并尝试在大鼠中进行基于生理的药代动力学（PBPK）建模。苏平诺辛具有良好的渗透性，在Caco-2细胞中与美托洛尔（高渗透性化合物）相当，观察到净吸收或分泌转运可忽略不计。在0.5-5mg/kg剂量范围内静脉注射后，苏平诺辛的末端半衰期（即2.54-2.80小时）、全身清除率（即691-865mL/h/kg）和稳态分布容积（即2040-3500mL/kg）保持不变，表明在所研究的剂量范围内药代动力学呈剂量无关（即剂量成比例）。口服给药后，苏平诺辛吸收适度，绝对口服生物利用度为56.9-57.4%。静脉注射和口服给药后的粪便回收率分别为16.5%和46.8%，而两种给药途径的尿液回收率可忽略不计。苏平诺辛主要通过NADPH依赖性I相代谢消除（即占总清除率的58.5%），而UDPGA依赖性II相代谢在大鼠肝微粒体中似乎可忽略不计。在所研究的九个主要组织（即脑、肝、肾、心、肺、脾、肠、肌肉和脂肪组织）中，苏平诺辛在脂肪组织、肠道和肝脏中分布最为丰富，并且基于生理的药代动力学能够很好地预测苏平诺辛的组织暴露情况。
