Lasiocarpine and riddelliine are pyrrolizidine alkaloids (PAs) present in food and able to cause liver toxicity. The aim of this study was to investigate whether physiologically based kinetic (PBK) modelling-facilitated reverse dosimetry can adequately translate in vitro concentration-response curves for toxicity of lasiocarpine and riddelliine to in vivo liver toxicity data for the rat. To this purpose, PBK models were developed for lasiocarpine and riddelliine, and predicted blood concentrations were compared to available literature data to evaluate the models. Concentration-response curves obtained from in vitro cytotoxicity assays in primary rat hepatocytes were converted to in vivo dose-response curves from which points of departure (PODs) were derived and that were compared to available literature data on in vivo liver toxicity. The results showed that the predicted PODs fall well within the range of PODs derived from available in vivo toxicity data. To conclude, this study shows the proof-of-principle for a method to predict in vivo liver toxicity for PAs by an alternative testing strategy integrating in vitro cytotoxicity assays with in silico PBK modelling-facilitated reverse dosimetry. The approach may facilitate prediction of acute liver toxicity for the large number of PAs for which in vivo toxicity data are lacking.

Lasiocarpine和riddelliine是存在于食品中的吡咯烷核生物碱（PAs），能够引起肝毒性。这项研究的目的是调查基于生理动力学（PBK）建模的反向剂量测定法是否可以将体外对Lasiocarpine和riddelliine的毒性的浓度-反应曲线充分转化为大鼠体内的肝毒性数据。为此，开发了用于Lasocarpine和riddelliine的PBK模型，并将预测的血药浓度与可用的文献数据进行比较以评估模型。从原代大鼠肝细胞的体外细胞毒性测定获得的浓度-响应曲线被转换为体内剂量-响应曲线，由此得出出发点（POD），并将其与有关体内肝毒性的现有文献数据进行了比较。结果表明，预测的POD很好地落在从可用的体内毒性数据得出的POD范围内。总而言之，这项研究显示了一种通过将体外细胞毒性测定与计算机PBK建模促进的反向剂量测定相结合的替代测试策略来预测PA的体内肝毒性的方法的原理证明。对于缺乏体内毒性数据的大量PA，该方法可能有助于预测其急性肝毒性。