Zhou Ning, Zheng Yuanting, Xing Junfen, Yang Huiying, Chen Hanmei, Xiang Xiaoqiang, Liu Jing, Tong Shanshan, Zhu Bin, Cai Weimin
Department of Clinical Pharmacy and Pharmaceutical Management, School of Pharmacy, Fudan University, Shanghai, China; and Shanghai BaiO Technology Company, Shanghai, China.
Department of Clinical Pharmacy and Pharmaceutical Management, School of Pharmacy, Fudan University, Shanghai, China; and Shanghai BaiO Technology Company, Shanghai, China
Drug Metab Dispos. 2016 Jan;44(1):40-9. doi: 10.1124/dmd.115.066092. Epub 2015 Oct 14.
Currently used in vitro models for estimating liver metabolism do not take into account the physiologic structure and blood circulation process of liver tissue. The Bio-PK metabolic system was established as an alternative approach to determine the in vitro intrinsic clearance of the model drug tolbutamide. The system contained a peristaltic pump, recirculating pipeline, reaction chamber, and rat liver microsomes (RLMs) encapsulated in pluronic F127-acrylamide-bisacrylamide (FAB) hydrogel. The metabolism of tolbutamide at initial concentrations of 100, 150, and 200 μM was measured in both the FAB hydrogel and the circular medium. The data from the FAB hydrogel and the circular medium were fitted to a mathematical model to obtain the predicted intrinsic clearance of tolbutamide after different periods of preincubation. The in vitro clearance value for tolbutamide was incorporated into Simcyp software and used to predict both the in vivo clearance value and the dynamic process of elimination. The predicted in vivo clearance of tolbutamide was 0.107, 0.087, and 0.095 L/h/kg for i.v. injection and 0.113, 0.095, and 0.107 L/h/kg for oral administration. Compared with the reported in vivo clearance of 0.09 L/h/kg (i.v.) and 0.10 L/h/kg (oral), all the predicted values differed by less than twofold. Thus, the Bio-PK metabolic system is a reliable and general in vitro model, characterized by three-dimensional structured RLM and circulation and perfusion processes for predicting the in vivo intrinsic clearance of low-extraction compounds, making the system more analogous with the rat in terms of both morphology and physiology.
目前用于评估肝脏代谢的体外模型未考虑肝脏组织的生理结构和血液循环过程。建立了生物药代动力学（Bio-PK）代谢系统，作为测定模型药物甲苯磺丁脲体外内在清除率的一种替代方法。该系统包含一个蠕动泵、循环管道、反应室以及包裹在普朗尼克F127-丙烯酰胺-双丙烯酰胺（FAB）水凝胶中的大鼠肝微粒体（RLMs）。在FAB水凝胶和循环介质中测定了初始浓度为100、150和200μM的甲苯磺丁脲的代谢情况。将来自FAB水凝胶和循环介质的数据拟合到一个数学模型中，以获得不同预孵育时间后甲苯磺丁脲的预测内在清除率。将甲苯磺丁脲的体外清除率值纳入Simcyp软件，用于预测体内清除率值和消除动态过程。甲苯磺丁脲静脉注射的预测体内清除率分别为0.107、0.087和0.095 L/h/kg，口服给药的预测体内清除率分别为0.113、0.095和0.107 L/h/kg。与报道的静脉注射体内清除率0.09 L/h/kg和口服体内清除率0.10 L/h/kg相比，所有预测值的差异均小于两倍。因此，Bio-PK代谢系统是一种可靠且通用的体外模型，其特征在于具有三维结构的RLM以及用于预测低摄取化合物体内内在清除率的循环和灌注过程，使得该系统在形态和生理方面与大鼠更为相似。
