Syngenta Ltd, Jealott's Hill International Research Centre, Bracknell, Berkshire RG42 6EY, UK.
Ramboll Environment and Health Consulting, 3214 Charles B. Root Wynd Suite 130, Raleigh, NC 27612, USA.
Toxicol Appl Pharmacol. 2021 Apr 15;417:115463. doi: 10.1016/j.taap.2021.115463. Epub 2021 Feb 22.
By extending our Paraquat (PQ) work to include primates we have implemented a modelling and simulation strategy that has enabled PQ pharmacokinetic data to be integrated into a single physiologically based pharmacokinetic (PBPK) model that enables more confident extrapolation to humans. Because available data suggested there might be differences in PQ kinetics between primates and non-primates, a radiolabelled study was conducted to characterize pharmacokinetics and excretion in Cynomolgus monkeys. Following single intravenous doses of 0.01 or 0.1 mg paraquat dichloride/kg bw, plasma PQ concentration-time profiles were dose-proportional. Excretion up to 48 h (predominantly urinary) was 82.9%, with ca. 10% remaining unexcreted. In vitro blood binding was similar across Cynomolgus monkeys, humans and rat. Our PBPK model for the rat, mouse and dog, employing a single set of PQ-specific parameters, was scaled to Cynomolgus monkeys and well represented the measured plasma concentration-time profiles over 14 days. Addition of a cartilage compartment to the model better captured the percent remaining in the monkeys at 48 h, whilst having negligible effect on model predictions for the other species. The PBPK model performed well for all four species, demonstrating there is little difference in PQ kinetics between non-primates and primates enabling a more confident extrapolation to humans. Scaling of the PBPK model to humans, with addition of a human-specific dermal submodel based on in vitro human dermal absorption data, provides a valuable tool that could be employed in defining internal dosimetry to complement human health risk assessments.
通过将百草枯（PQ）工作扩展到包括灵长类动物，我们实施了一种建模和模拟策略，使 PQ 药代动力学数据能够整合到单个生理相关药代动力学（PBPK）模型中，从而能够更有信心地外推到人类。由于现有数据表明灵长类动物和非灵长类动物之间的 PQ 动力学可能存在差异，因此进行了一项放射性标记研究，以表征食蟹猴中的药代动力学和排泄。在单次静脉注射 0.01 或 0.1 mg 百草枯二氯盐/公斤体重后，血浆 PQ 浓度-时间曲线与剂量成正比。48 小时内（主要通过尿液）排泄 82.9%，约 10%未排泄。食蟹猴、人类和大鼠的体外血液结合相似。我们的大鼠、小鼠和犬的 PBPK 模型，使用一组特定的 PQ 参数，可扩展到食蟹猴，并很好地代表了 14 天内测量的血浆浓度-时间曲线。在模型中添加软骨隔室可以更好地捕捉到 48 小时后猴子体内的剩余百分比，而对其他物种的模型预测几乎没有影响。该 PBPK 模型在所有四个物种中表现良好，表明非灵长类动物和灵长类动物之间的 PQ 动力学差异很小，能够更有信心地外推到人类。将 PBPK 模型扩展到人类，并添加基于体外人类皮肤吸收数据的人类特异性皮肤子模型，为定义内部剂量学提供了有价值的工具，可用于补充人类健康风险评估。
