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 (C_max), area under the concentration-time curve (AUC), time to reach the maximum plasma concentration (T_max) 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.

中文翻译：

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新型体外动态代谢系统，可预测甲苯磺丁酰胺的人体药代动力学。

肝脏代谢通常被认为是药物发现和开发的主要决定因素。已经开发了许多体外药物代谢研究并将其应用于了解生物转化。然而，这些方法具有缺点，导致体内和体外实验之间的不一致。一个主要因素是它们是静态系统，不考虑肝脏中的转运过程。在这里，我们开发了一种体外动态代谢系统（Bio-PK代谢系统），以模拟甲苯磺丁酰胺的人体药代动力学。将封装在F127'-Acr-Bis水凝胶（FAB水凝胶）中的人肝微粒体（HLM）置于培养系统中。微透析采样技术用于监测水凝胶中甲苯磺丁酰胺的代谢行为。系统中的测量结果用于通过数学模型拟合甲苯磺丁酰胺的体外固有清除率。然后，开发了一个整合了相应的体外固有清除率的PBPK模型来验证该系统。与传统的孵育方法相比，通过将从Bio-PK代谢系统获得的甲苯磺丁酰胺的固有清除率整合到PBPK模型中，可以预测合理的PK分布和甲苯磺丁酰胺的体内清除率。预测最大浓度（C 通过将从Bio-PK代谢系统获得的甲苯磺丁酰胺的固有清除率整合到PBPK模型中，可以预测合理的PK分布和甲苯磺丁酰胺的体内清除率。预测最大浓度（C 通过将从Bio-PK代谢系统获得的甲苯磺丁酰胺的固有清除率整合到PBPK模型中，可以预测合理的PK分布和甲苯磺丁酰胺的体内清除率。预测最大浓度（C_max），浓度-时间曲线下的面积（AUC），达到最大血浆浓度的时间（T _max）和体内清除率与临床观察到的数据一致。这种新颖的体外动态代谢系统可以弥补传统孵育方法的一些局限性。它可能为早期筛选化合物和预测药代动力学提供一种新方法，从而支持化合物的开发。