Article

Novel in vitro dynamic metabolic system for predicting the human pharmacokinetics of tolbutamide

Authors: Cai-fu XUE1, Zhe ZHANG1, Yan JIN1, Bin ZHU2, Jun-fen XING2, Guo MA1, Xiao-qiang XIANG1, Wei-min CAI1
1 Department of Clinical Pharmacy, School of Pharmacy, Fudan University, Shanghai 201203, China
2 Shanghai BaiO Technology Company, Shanghai 200233, China
Corresponding to: Wei-min CAI: weimincai@fudan.edu.cn,
DOI: 10.1038/aps.2017.201
Received: 24 August 2017
Accepted: 9 December 2017
Advance online: 12 April 2018

Abstract

Liver metabolism is commonly considered the major determinant in drug discovery and development. Many in vitro drug metabolic studies have been developed and applied to understand biotransformation. However, these methods have disadvantages, resulting in inconsistencies between in vivo and in vitro experiments. A major factor is that they are static systems that do not consider the transport process in the liver. Here we developed an in vitro dynamic metabolic system (Bio-PK metabolic system) to mimic the human pharmacokinetics of tolbutamide. Human liver microsomes (HLMs) encapsulated in a F127’-Acr-Bis hydrogel (FAB hydrogel) were placed in the incubation system. A microdialysis sampling technique was used to monitor the metabolic behavior of tolbutamide in hydrogels. The measured results in the system were used to fit the in vitro intrinsic clearance of tolbutamide with a mathematical model. Then, a PBPK model that integrated the corresponding in vitro intrinsic clearance was developed to verify the system. Compared to the traditional incubation method, reasonable PK profiles and the in vivo clearance of tolbutamide could be predicted by integrating the intrinsic clearance of tolbutamide obtained from the Bio-PK metabolic system into the PBPK model. The predicted maximum concentration (Cmax), area under the concentration-time curve (AUC), time to reach the maximum plasma concentration (Tmax) and in vivo clearance were consistent with the clinically observed data. This novel in vitro dynamic metabolic system can compensate for some limitations of traditional incubation methods; it may provide a new method for screening compounds and predicting pharmacokinetics in the early stages, supporting the development of compounds.
Keywords: physiologically based pharmacokinetic model; FAB hydrogel; microdialysis; tolbutamide; Bio-PK metabolic system; dynamic; human liver microsomes

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