Department of Analytical Environmental Chemistry , Helmholtz Centre for Environmental Research UFZ , Permoserstr. 15 , 04318 Leipzig , Germany.
Institute of Chemistry , University of Halle-Wittenberg , Kurt-Mothes-Str. 2 , 06120 Halle , Germany.
Chem Res Toxicol. 2018 Nov 19;31(11):1195-1202. doi: 10.1021/acs.chemrestox.8b00187. Epub 2018 Oct 12.
The extrapolation of metabolism data from in vitro experiments to in vivo clearances can provide useful information in the fields of pharmacokinetics and toxicokinetics. Depending on the purpose, different toxicokinetic models are used, and these different models require the in vivo metabolic information in different forms. In this study, a comprehensive toolbox for in vitro- in vivo extrapolation (IVIVE) of hepatic metabolism is presented addressing a variety of different extrapolation goals: extrapolation to hepatic blood clearance, extrapolation to organ clearance, extrapolation to whole-body clearance, and extrapolation to clearance at the level of hepatocytes. The use of the extrapolated clearances for calculation of extraction efficiencies and the use in physiologically based pharmacokinetic models are discussed. Furthermore, a sensitivity analysis demonstrates which parameters affect the accuracy of the extrapolation results the most, and the presented extrapolation procedure is evaluated by comparison to experimental data from perfused liver experiments.
从体外实验推断代谢数据到体内清除率可以在药代动力学和毒代动力学领域提供有用的信息。根据目的的不同，使用不同的毒代动力学模型，这些不同的模型以不同的形式需要体内代谢信息。在这项研究中，提出了一个全面的体外-体内外推（IVIVE）肝脏代谢工具包，用于解决各种不同的外推目标：从肝血流清除率外推，从器官清除率外推，从全身清除率外推，以及从肝细胞水平的清除率外推。讨论了外推清除率用于计算提取效率的用途以及在基于生理学的药代动力学模型中的用途。此外，敏感性分析表明哪些参数对推断结果的准确性影响最大，并通过与灌注肝实验的实验数据进行比较来评估所提出的外推程序。
