应用ERDEM模型为涕灭威及其代谢物构建大鼠和人的PBPK/PD模型研究

摘要

Objective To construct the PBPK/PD models for aldicarb in rats and humans to help understandits disposition in both species in order to use the models for risk assessment purposes due to aldicarb exposure. MethodsThe PBPK/PD models were constructed using the ERDEM ( Exposure-related dose estimating model ) platform. Themodel structures for both species included a full gastrointestinal compartment, liver metabolism, urinary excretion, fecalelimination,and bimolecular acetylcholinesterase ( AChE ) inhibition by aldicarb and its two oxidized metabolites, aldi-carb sulfoxide and aldicarb sulfone. Experimentally reported values or estimation of physiological, biochemical, and physicochemical parameters were obtained from the open literature or optimized by fitting to the experimental data. Results The rat model simulation of oral exposure of 0. 4 mg/kg aldicarb indicated that aldicarb had an overall half-life of 1. 35 h,and 96. 6% of the dose was excreted in urine compared to the measured 91. 6% at 144 h after oral exposure. AChE activity in blood was inhibited to 31 % of the control level at 0. 35 h in the rat model compared to the measured 42. 5% at 0. 5 h after oral exposure of 0. 33 mg/kg aldicarb. In the human model,the simulation showed that the minimum blood AChE activity was 76. 9% at 1 h compared to the measured 75. 3% after a 0. 05 mg/kg dose of aldicarb. Conclusion The ERDEM model simulations for both species were consistent with the experimental data. Therefore, the models constructed in the ERDEM platform may be helpful in evaluating human health risk due to aldicarb exposure.%目的 为构建涕灭威在大鼠和人的生理药代动力学/药效学(PBPK/PD)模型,以进一步了解涕灭威在两物种体内的转化过程,从而用于其风险评估.方法 采用暴露相关的剂量估算模型(Exposure-related dose estimating model,ERDEM)的构建平台进行模型构建.两个物种的模型结构均包括完整的胃肠道、肝脏代谢、尿排泄、粪便消除以及涕灭威和两个氧化代谢产物-涕灭威砜和涕灭威亚砜所致的双分子模式的乙酰胆碱酯酶(AChE)抑制.模型的生理、生化和物理化学参数值从公开文献中获得或者通过对实验数据的拟合后优化而成.结果 大鼠模型的模拟表明,经口给药0.4 mg/kg的涕灭威的整体半衰期为1.35 h;96.6%的暴露剂量(对比实测值91.6%)于给药后144 h从尿中排出;经口给药0.33 mg/kg,血液最低AChE活性被抑制(0.35 h时,为正常对照的31%,对比实测的0.5 h 42.5%).人体模型模拟经口暴露涕灭威0.05 mg/kg表明,血中最低AChE活性在1 h时为正常对照的76.9%(对比测得值75.3%).结论 模拟表明,模型预测与实验数据基本一致.因此,在ERDEM中构建的PBPK/PD模型有助于因涕灭威暴露而进行的健康风险评估.