A physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) model for the insecticide dimethoate

1. Dimethoate is an organophosphate insecticide that is converted <i>in vivo</i> to omethoate, the active toxic moiety. Omethoate inhibits acetylcholinesterase (AChE) in the brain and red blood cells (RBCs). This paper describes the development of rat and human physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) models for dimethoate. 2. The model simulates the absorption and distribution of dimethoate and omethoate, the conversion of dimethoate to omethoate and to other metabolites, the metabolism and excretion of omethoate, and the inhibition of RBC and brain AChE. An extensive data collection program to estimate metabolism and inhibition parameters is described. 3. The suite of models includes an adult rat, post-natal rat, and human model. The rat models were evaluated by comparing model predictions of dimethoate and omethoate to measured blood time course data, and with RBC and brain AChE inhibition estimates from an extensive database of <i>in vivo</i> AChE measurements. 4. After the demonstration of adequately fitted rat models that were robust to sensitivity analysis, the human model was applied for estimation of points-of-departure (PODs) for risk assessment using the human-specific parameters in the human PBPK/PD model. Thus, the standard interspecies uncertainty factor can be reduced from 10X to 1X.

1. 乐果（Dimethoate）是一种有机磷杀虫剂，可在体内（in vivo）转化为氧化乐果（omethoate）——其为该药剂具备毒性活性的基团。氧化乐果会抑制大脑与红细胞（RBCs）中的乙酰胆碱酯酶（AChE）。本文阐述了针对乐果的大鼠与人类生理学药代动力学/药效学（PBPK/PD）模型的构建工作。
2. 该模型可模拟乐果与氧化乐果的吸收与分布、乐果向氧化乐果及其他代谢产物的转化过程、氧化乐果的代谢与排泄路径，以及红细胞与大脑乙酰胆碱酯酶的抑制效应。文中同时描述了一项用于估算代谢与抑制参数的大规模数据采集计划。
3. 该模型集涵盖成年大鼠模型、新生大鼠模型以及人类模型。通过将乐果与氧化乐果的模型预测结果与实测血液时间进程数据进行比对，并结合来自大规模体内（in vivo）乙酰胆碱酯酶测量数据库的红细胞与大脑乙酰胆碱酯酶抑制估算结果，完成了对大鼠模型的验证。
4. 在证明拟合效果优异的大鼠模型经敏感性分析验证具备良好稳健性后，研究人员借助人类PBPK/PD模型中的人类特异性参数，将人类模型应用于风险评估所需的剂量出发点（PODs）估算。由此，标准种间不确定因子可从10倍缩减至1倍。