Wageningen Food Safety Research (WFSR), part of Wageningen University and Research, Wageningen, the Netherlands.
Wageningen Food Safety Research (WFSR), part of Wageningen University and Research, Wageningen, the Netherlands.
Toxicol In Vitro. 2020 Mar;63:104722. doi: 10.1016/j.tiv.2019.104722. Epub 2019 Nov 20.
Non-animal methods for toxicokinetics, such as in vitro hepatic metabolic clearance studies, play an important role in chemical risk evaluations. To gain regulatory acceptance of such clearance data, the development of a test guideline for performing in vitro hepatic clearance studies is crucial. The aim of the present study was to obtain insight in the experimental conditions of clearance studies that influence obtained intrinsic clearance (CLint) values. To that end, in vitro hepatic CLint data obtained with rat or human hepatocytes and methodological aspects of the experiments, were collected from 42 different suitable studies published between 1995 and 2018. The CLint values for the majority of chemicals differed by more than one order of magnitude. We estimated the systematic effect of different experimental setups on the CLint values using a random forest regression analysis, revealing that 'hepatocyte concentration', 'species' (rat or human hepatocytes) and 'culture medium' have the largest impact. Calculating unbound CLint (CLint,u) values slightly reduced the variation for most chemicals. Given that in vivo clearance is in general underpredicted based on in vitro clearance data, a harmonized protocol is preferably based on a protocol that provides relatively high in vitro CLint values.
非动物毒代动力学方法，如体外肝代谢清除研究，在化学风险评估中起着重要作用。为了使此类清除数据得到监管部门的认可，制定进行体外肝清除研究的试验指南至关重要。本研究的目的是了解影响获得的内在清除率（CLint）值的清除研究的实验条件。为此，从 1995 年至 2018 年发表的 42 项合适的研究中收集了用大鼠或人肝细胞进行的体外肝 CLint 数据以及实验的方法学方面。大多数化学物质的 CLint 值相差一个以上数量级。我们使用随机森林回归分析估计了不同实验设置对 CLint 值的系统影响，结果表明“肝细胞浓度”、“物种”（大鼠或人肝细胞）和“培养基”的影响最大。计算未结合的 CLint（CLint,u）值可使大多数化学物质的变异性略有降低。鉴于基于体外清除数据，体内清除通常被低估，因此，优选基于提供相对较高体外 CLint 值的方案的协调方案。
