Andersen M E
K.S. Crump Division, ICF Kaiser International, Morrisville, NC 27560, USA.
Toxicol Lett. 1995 Sep;79(1-3):35-44. doi: 10.1016/0378-4274(95)03355-o.
Pharmacokinetics (PK) involves the study of the rates of absorption, distribution, excretion, and biotransformation of chemicals and their metabolites. PK models can be used to reconstruct extensive time-course data sets based on a small number of kinetic parameters. These models can be used to predict the results of new experiments and integrate studies on kinetics, disposition and metabolism in various animal species [1]. The 2 main approaches that have been pursued in developing PK models are: (1) data-based compartmental modeling; and (2) physiologically based compartmental modeling. Data-based models rely on the collection of time-course concentration data and fitting these data with mathematical models. Compartments in these models do not necessarily reflect the anatomy and physiology of the animal, and the kinetic constants derived from these models do not have obvious physiological or biochemical counterparts. In physiologically based pharmacokinetic (PBPK) models, compartments correspond more closely to actual anatomical structures, defined with respect to their volumes, blood flows, chemical binding (partitioning) characteristics, and ability to metabolize or excrete the compounds of interest. Because the kinetic parameters of these models reflect tissue blood flows, partitioning, and biochemical constants, these models are more readily scaled from one animal species to another [2]. PBPK models have been used to understand the disposition of chemicals in the body for almost 70 years. Their more widespread application in toxicology dates back only 15 years or so to models developed for polychlorinated biphenyls and other persistent lipophilic compounds. Quantitative applications of PBPK models in risk assessment date to the development of a number of PBPK models for methylene chloride in the mid 1980s. The burgeoning use of PBPK models in toxicology research and chemical risk assessment today is primarily related to their ability to make more accurate predictions of target tissue dose for different exposure situations in different animal species, including humans. This overview includes a discussion of the development of these PBPK models in toxicology and speculates about future applications of PBPK and physiologically based pharmacodynamic (PBPD) models in chemical risk assessment.
药代动力学（PK）涉及对化学物质及其代谢产物的吸收、分布、排泄和生物转化速率的研究。PK模型可用于基于少量动力学参数重建大量的时间进程数据集。这些模型可用于预测新实验的结果，并整合各种动物物种的动力学、处置和代谢研究[1]。在开发PK模型时所采用的两种主要方法是：（1）基于数据的房室建模；以及（2）基于生理学的房室建模。基于数据的模型依赖于时间进程浓度数据的收集，并将这些数据与数学模型进行拟合。这些模型中的房室不一定反映动物的解剖结构和生理学，并且从这些模型得出的动力学常数没有明显的生理或生化对应物。在基于生理学的药代动力学（PBPK）模型中，房室与实际解剖结构的对应更为紧密，根据其体积、血流量、化学结合（分配）特性以及代谢或排泄目标化合物的能力来定义。由于这些模型的动力学参数反映了组织血流量、分配和生化常数，因此这些模型更容易从一种动物物种扩展到另一种动物物种[2]。PBPK模型已被用于了解化学物质在体内的处置情况近70年了。它们在毒理学中的更广泛应用仅可追溯到大约15年前为多氯联苯和其他持久性亲脂性化合物开发的模型。PBPK模型在风险评估中的定量应用可追溯到20世纪80年代中期为二氯甲烷开发的一些PBPK模型。如今，PBPK模型在毒理学研究和化学风险评估中的迅速应用主要与其能够更准确地预测不同动物物种（包括人类）在不同暴露情况下的靶组织剂量有关。本综述包括对这些PBPK模型在毒理学中的发展讨论，并推测了PBPK和基于生理学的药效学（PBPD）模型在化学风险评估中的未来应用。
