van Eijkeren Jan C H
National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
Risk Anal. 2002 Feb;22(1):159-73. doi: 10.1111/0272-4332.t01-1-00013.
A mechanistic model is presented describing the clearance of a compound in a precision-cut liver slice that is incubated in a culture medium. The problem of estimating metabolic rate constants in PBPK models from liver slice experiments is discussed using identifiability analysis. From the identifiability problem analysis, it appears that in addition to the clearance, the compound's free fraction in the slice and the diffusion rate of the exchange of the compound between culture medium and liver slice should be identified. In addition, knowledge of the culture medium volume, the slice volume, the compound's free fraction, and octanol-water-based partition between medium and slice is presupposed. The formal solution for identification is discussed from the perspective of experimental practice. A formally necessary condition for identification is the sampling of parent compound in liver slice or culture medium. However, due to experimental limitations and errors, sampling the parent compound in the slice together with additional sampling of metabolite pooled from the medium and the slice is required for identification in practice. Moreover, it appears that identification results are unreliable when the value of the intrinsic clearance exceeds the value of the diffusion coefficient, a condition to be verified a posteriori.
本文提出了一个机理模型，用于描述在培养基中孵育的精密肝切片中化合物的清除情况。利用可识别性分析讨论了从肝切片实验估计生理药代动力学（PBPK）模型中代谢速率常数的问题。从可识别性问题分析来看，除清除率外，似乎还应确定化合物在切片中的游离分数以及化合物在培养基和肝切片之间交换的扩散速率。此外，还预先假定了培养基体积、切片体积、化合物的游离分数以及培养基和切片之间基于正辛醇 - 水的分配系数等知识。从实验实践的角度讨论了识别的形式解。识别的一个形式上必要条件是在肝切片或培养基中对母体化合物进行采样。然而，由于实验限制和误差，在实践中识别需要在切片中对母体化合物进行采样，并额外对从培养基和切片中收集的代谢物进行采样。此外，当固有清除率的值超过扩散系数的值时，识别结果似乎不可靠，这一条件需要事后验证。
