Development of a physiologically based pharmacokinetic model for perchloroethylene using tissue concentration-time data.
Development of a physiologically based pharmacokinetic model for perchloroethylene using tissue concentration-time data.
复制标题
使用组织浓度-时间数据开发基于生理学的全氯乙烯药代动力学模型。
DOI：
10.1006/taap.1994.1179
复制
发表时间：
1994
影响因子：
3.8
通讯作者：
J. Bruckner
中科院分区：
文献类型：
--
作者：
C. Dallas;Xiao Mei Chen;K. O'Barr;S. Muralidhara;P. Várkonyi;J. Bruckner
在大鼠中对全氯乙烯 (PCE) 的组织分布进行实验表征，以便 (1) 从体内数据获取输入参数，用于开发基于生理学的药代动力学 (PBPK) 模型，以及 (2) 使用 PBPK 模型预测吸入暴露后 PCE 在各种组织中的沉积。为了推导模型输入参数，雄性Sprague-Dawley大鼠通过留置颈动脉插管接受单次推注10mg PCE/kg体重的聚乙二醇400溶液。其他雄性 Sprague-Dawley 大鼠在动态暴露吸入室中吸入 500 ppm PCE 2 小时。 ia注射后72小时内、2小时吸入暴露期间以及暴露后72小时内采集脑、肝、肾、肺、心脏、骨骼肌、肾周脂肪和血液的系列样本。使用气相色谱顶空技术分析血液和组织中的四氯乙烯浓度。 ia施用后，组织表现出相似的终末消除半衰期(t1/2)。由于可比较的组织 t1/2 与血流限制模型一致，因此通过用组织浓度-时间曲线 (AUC) 下的面积除以血液 AUC 来计算非消除区室的组织：血液分配系数。肝脏 PCE 浓度与时间的关系数据用于计算体内代谢率常数。使用源自 ia 数据集的这些参数开发了 PBPK 模型，并用于预测 PCE 吸入期间和之后的组织 PCE 浓度。预测的组织水平与七种组织和血液中随着时间的推移测量的水平非常一致。因此，只要每个步骤使用独立的体内数据集，组织浓度-时间数据就可以为参数估计和 PBPK 模型模拟验证提供有价值的输入。
The tissue disposition of perchloroethylene (PCE) was characterized experimentally in rats in order to (1) obtain input parameters from in vivo data for the development of a physiologically based pharmacokinetic (PBPK) model, and (2) use the PBPK model to predict the deposition of PCE in a variety of tissues following inhalation exposure. For the derivation of model input parameters, male Sprague-Dawley rats received a single bolus of 10 mg PCE/kg body wt in polyethylene glycol 400 by ia injection through an indwelling carotid arterial cannula. Other male Sprague-Dawley rats inhaled 500 ppm PCE for 2 hr in dynamic exposure inhalation chambers. Serial samples of brain, liver, kidney, lung, heart, skeletal muscle, perirenal fat, and blood were taken for up to 72 hr following ia injection, during the 2-hr inhalation exposure, and for up to 72 hr postexposure. Blood and tissue PCE concentrations were analyzed using a gas chromatography headspace technique. Following ia administration, the tissues exhibited similar terminal elimination half-lives (t1/2). As comparable tissue t1/2 are consistent with a blood-flow-limited model, tissue:blood partition coefficients were calculated for noneliminating compartments by division of the area under the tissue concentration-time curve (AUC) by the blood AUC. Liver PCE concentration versus time data were employed in the calculation of in vivo metabolic rate constants. A PBPK model was developed using these parameters derived from the ia data set and used to predict tissue PCE concentrations during and following PCE inhalation. Predicted tissue levels were in close agreement with the levels measured over time in the seven tissues and in blood. Tissue concentration-time data can thus provide valuable input for parameter estimation and for validation of PBPK model simulations, as long as independent in vivo data sets are used for each step.