The aim of the present study was to use an in vitro–in silico approach to predict the in vivo acute liver toxicity of monocrotaline and to characterize the influence of its metabolism on its relative toxic potency compared to lasiocarpine and riddelliine. In the absence of data on acute liver toxicity of monocrotaline upon oral exposure, the predicted dose–response curve for acute liver toxicity in rats and the resulting benchmark dose lower and upper confidence limits for 10% effect (BMDL₁₀ and BMDU₁₀) were compared to data obtained in studies with intraperitoneal or subcutaneous dosing regimens. This indicated the predicted BMDL₁₀ value to be in line with the no-observed-adverse-effect levels (NOAELs) derived from availabe in vivo studies. The predicted BMDL₁₀–BMDU₁₀ of 1.1–4.9 mg/kg bw/day also matched the oral dose range of 1–3 mg PA/kg bw/day at which adverse effects in human are reported. A comparison to the oral toxicity of the related pyrrolizidine alkaloids (PAs) lasiocarpine and riddelliine revealed that, although in the rat hepatocytes monocrotaline was less toxic than lasiocarpine and riddelliine, due to its relatively inefficient clearance, its in vivo acute liver toxicity was predicted to be comparable. It is concluded that the combined in vitro-PBK modeling approach can provide insight in monocrotaline-induced acute liver toxicity in rats, thereby filling existing gaps in the database on PA toxicity. Furthermore, the results reveal that the kinetic and metabolic properties of PAs can vary substantially and should be taken into account when considering differences in relative potency between different PAs.

本研究的目的是使用体外-计算机模拟方法来预测单芥子碱的体内急性肝毒性，并表征其代谢相对于Lascarcarpine和riddelliine的相对毒性。由于缺乏对角氯丁胺经口服的急性肝毒性数据的比较，比较了大鼠急性肝毒性的预测剂量-反应曲线以及所产生的10％效应的基准剂量上下限（BMDL ₁₀和BMDU ₁₀）。腹膜内或皮下给药方案研究中获得的数据。这表明预测的BMDL ₁₀该值与从体内研究得出的未观察到的不良反应水平（NOAEL）一致。预测的BMDL ₁₀ –BMDU ₁₀1.1–4.9 mg / kg bw /天的口服剂量范围也符合1-3 mg PA / kg bw /天的口服剂量范围，据报道该剂量对人有不良影响。与相关吡咯并立烷生物碱（拉索卡地碱和利地奈林）的口服毒性比较表明，尽管在大鼠肝细胞中，单芥子碱的毒性低于拉西卡因和里地奈林，但由于其清除效率相对较低，预计其体内急性肝毒性会可比。结论是，结合体外-PBK建模方法可以提供洞察克罗他林诱导的大鼠急性肝毒性，从而填补了PA毒性数据库中的现有空白。此外，