A physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model for the organophosphate insecticide chlorpyrifos in rats and humans
A physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model for the organophosphate insecticide chlorpyrifos in rats and humans
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DOI：
10.1093/toxsci/66.1.34
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发表时间：
2002-03-01
影响因子：
3.8
通讯作者：
Mattsson, JL
中科院分区：
文献类型：
--
作者：
Timchalk, C;Nolan, RJ;Mattsson, JL
建立了有机磷杀虫剂毒死蜱（CPF）及其主要代谢产物氧磷（oxon）和3，5，6-三氯-2-吡啶酚（TCP）在大鼠和人体内的PBPK/PD模型。该模型集成了靶组织剂量测定和动态响应（即，酯酶抑制），描述急性和慢性口服和皮肤接触后，CPF、CPF-oxon和TCP在血液和组织中的吸收、代谢和处置以及相关的胆碱酯酶（ChE）抑制动力学。为了促进模型开发，在大鼠（0.5-100 mg/kg）和人（0.5-2 mg/kg）中进行了单次口服给药的药代动力学研究，并测定了CPF、CPF-oxon和TCP的动力学，以及血液（血浆/RBC）和脑（仅大鼠）ChE抑制的程度。在血液中，分析物的浓度遵循TCP > > CPF > > CPF-oxon的顺序;在人体中，CPF-oxon无法定量。模拟与实验数据和先前发表的大鼠和人类研究进行了比较。该模型被用来定量比较大鼠和人类之间的剂量测定和动态响应在一定范围内的CPF剂量。CPF和TCP在这两个物种的时间过程是线性的剂量范围内评估，该模型合理地模拟血浆胆碱酯酶，红细胞乙酰胆碱酯酶（AChE），和脑（大鼠）AChE的剂量依赖性抑制。模型模拟表明，大鼠表现出更大的代谢CPF CPF-氧磷比人类做，和非目标B-酯酶的消耗与CPF-氧磷血液和脑浓度的非线性，剂量依赖性增加。这CPF PBPK/PD模型定量估计靶组织剂量测定和乙酰胆碱酯酶抑制，是一个强有力的框架，进一步有机磷（OP）模型的开发和完善生物为基础的风险评估暴露于CPF在各种情况下。
A PBPK/PD model was developed for the organophosphate insecticide chlorpyrifos (CPF) (O,O-diethyl-O-[3,5,6-trichloro-2-pyridyl]phosphorothioate), and the major metabolites CPF-oxon and 3,5,6-trichloro-2-pyridinol (TCP) in rats and humans. This model integrates target tissue dosimetry and dynamic response (i.e., esterase inhibition) describing uptake, metabolism, and disposition of CPF, CPF-oxon, and TCP and the associated cholinesterase (ChE) inhibition kinetics in blood and tissues following acute and chronic oral and dermal exposure. To facilitate model development, single oral-dose pharmacokinetic studies were conducted in rats (0.5-100 mg/kg) and humans (0.5-2 mg/kg), and the kinetics of CPF, CPF-oxon, and TCP were determined, as well as the extent of blood (plasma/RBC) and brain (rats only) ChE inhibition. In blood, the concentration of analytes followed the order TCP > > CPF > > CPF-oxon; in humans CPF-oxon was not quantifiable. Simulations were compared against experimental data and previously published studies in rats and humans. The model was utilized to quantitatively compare dosimetry and dynamic response between rats and humans over a range of CPF doses. The time course of CPF and TCP in both species was linear over the dose range evaluated, and the model reasonably simulated the dose-dependent inhibition of plasma ChE, RBC acetylcholinesterase (AChE), and brain (rat only) AChE. Model simulations suggest that rats exhibit greater metabolism of CPF to CPF-oxon than humans do, and that the depletion of nontarget B-esterase is associated with a nonlinear, dose-dependent increase in CPF-oxon blood and brain concentration. This CPF PBPK/PD model quantitatively estimates target tissue dosimetry and AChE inhibition and is a strong framework for further organophosphate (OP) model development and for refining a biologically based risk assessment for exposure to CPF under a variety of scenarios.