title: Application of a New Dynamic Model to Predict the In Vitro Intrinsic Clearance of Tolbutamide Using Rat Microsomes Encapsulated in a Fab Hydrogel.
abstract: 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.
authors.affiliation: Department of Clinical Pharmacy and Pharmaceutical Management, School of Pharmacy, Fudan University, Shanghai, China; and Shanghai BaiO Technology Company, Shanghai, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhou
authors.affiliation: Department of Clinical Pharmacy and Pharmaceutical Management, School of Pharmacy, Fudan University, Shanghai, China; and Shanghai BaiO Technology Company, Shanghai, China.
authors.forename: Yuanting
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Clinical Pharmacy and Pharmaceutical Management, School of Pharmacy, Fudan University, Shanghai, China; and Shanghai BaiO Technology Company, Shanghai, China.
authors.forename: Junfen
authors.initials: J
authors.lastname: Xing
authors.affiliation: Department of Clinical Pharmacy and Pharmaceutical Management, School of Pharmacy, Fudan University, Shanghai, China; and Shanghai BaiO Technology Company, Shanghai, China.
authors.forename: Huiying
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Clinical Pharmacy and Pharmaceutical Management, School of Pharmacy, Fudan University, Shanghai, China; and Shanghai BaiO Technology Company, Shanghai, China.
authors.forename: Hanmei
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Clinical Pharmacy and Pharmaceutical Management, School of Pharmacy, Fudan University, Shanghai, China; and Shanghai BaiO Technology Company, Shanghai, China.
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Xiang
authors.affiliation: Department of Clinical Pharmacy and Pharmaceutical Management, School of Pharmacy, Fudan University, Shanghai, China; and Shanghai BaiO Technology Company, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Clinical Pharmacy and Pharmaceutical Management, School of Pharmacy, Fudan University, Shanghai, China; and Shanghai BaiO Technology Company, Shanghai, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Tong
authors.affiliation: Department of Clinical Pharmacy and Pharmaceutical Management, School of Pharmacy, Fudan University, Shanghai, China; and Shanghai BaiO Technology Company, Shanghai, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhu
authors.affiliation: Department of Clinical Pharmacy and Pharmaceutical Management, School of Pharmacy, Fudan University, Shanghai, China; and Shanghai BaiO Technology Company, Shanghai, China weimincai@fudan.edu.cn.
authors.forename: Weimin
authors.initials: W
authors.lastname: Cai
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004058:Diffusion; D020100:Hydrogels / Q000737:chemistry*; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000378:metabolism*; D007260:Infusion Pumps; D007275:Injections, Intravenous; D007700:Kinetics; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000201:enzymology* / Q000378:metabolism; D008954:Models, Biological; D051381:Rats; D015203:Reproducibility of Results; D014044:Tolbutamide / Q000008:administration & dosage / Q000378:metabolism*
chemical_list: D020100:Hydrogels; D007004:Hypoglycemic Agents; D014044:Tolbutamide