Dallas C E, Chen X M, O'Barr K, Muralidhara S, Varkonyi P, Bruckner J V
Department of Pharmacology and Toxicology, College of Pharmacy, University of Georgia, Athens 30602-2356.
Toxicol Appl Pharmacol. 1994 Sep;128(1):50-9. doi: 10.1006/taap.1994.1179.
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.
为了（1）从体内数据中获取输入参数以建立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全氯乙烯（PCE）在各种组织中的沉积情况，对大鼠体内PCE的组织分布进行了实验表征。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经腹腔注射10 mg PCE/kg体重的聚乙二醇400单次大剂量给药。其他雄性Sprague-Dawley大鼠在动态暴露吸入舱中吸入500 ppm PCE 2小时。在腹腔注射后长达72小时、2小时吸入暴露期间以及暴露后长达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PCE浓度。腹腔给药后，各组织表现出相似的终末消除半衰期（t1/2）。由于可比的组织t1/2与血流限制模型一致，通过将组织浓度-时间曲线下面积（AUC）除以血液AUC，计算非消除隔室的组织：血液分配系数。利用肝脏PCE浓度随时间变化的数据计算体内代谢速率常数。使用从腹腔注射数据集得出的这些参数建立了一个PBPK模型，并用于预测PCE吸入期间及之后的组织PCE浓度。预测的组织水平与七个组织和血液中随时间测量的水平密切一致。因此，只要在每个步骤中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模型模拟的验证提供有价值的输入。
