Haenen Bert, Rompelberg Cathy, van Twillert Klaas, Hamzink Martin, Dormans Jan, van Eijkeren Jan
Laboratory of Exposure Assessment and Environmental Epidemiology, National Institute of Public Health and the Environment, Bilthoven, The Netherlands.
Drug Metab Dispos. 2002 Mar;30(3):307-13. doi: 10.1124/dmd.30.3.307.
Liver slice experiments were performed to determine the slice intrinsic clearance and to extrapolate this to the in vivo liver intrinsic clearance in a physiologically based pharmacokinetic (PBPK)-like approach. Precision-cut liver slices were incubated with different initial concentrations of tolbutamide, and the time series of parent and metabolite concentrations were measured in slice and incubation medium. A mathematical model was built that modeled the uptake of tolbutamide and its metabolism in the liver slice. In addition, binding of tolbutamide to cellular constituents and partition over the water and lipid phase were accounted for by the model. Model analysis imposed sampling of parent compound in slice and of metabolites pooled from slice and medium. The model was calibrated to the data, fitting the intrinsic clearance, the parent compounds' free fraction in liver material, and a diffusion parameter describing medium-slice exchange of tolbutamide. In addition, to ensure a meaningful application of the theoretical model, slice viability parameters were monitored before and during the experiment. For the different incubations, the intrinsic clearance per unit of volume of slice ranged from 0.035 to 0.086 min(-1) when not correcting for slice viability and from 0.044 to 0.11 min(-1) when correcting for slice viability. The results were extrapolated to a PBPK model for tolbutamide in the rat. The value for the intrinsic clearance found by calibrating the PBPK model to previous in vivo data was 0.090 min(-1). This result suggests that liver slices are a valuable tool for predicting in vivo intrinsic clearance of low-extraction compounds.
进行肝脏切片实验以确定切片固有清除率，并采用基于生理学的药代动力学（PBPK）类似方法将其外推至体内肝脏固有清除率。将精密切割的肝脏切片与不同初始浓度的甲苯磺丁脲一起孵育，并测量切片和孵育介质中母体和代谢物浓度的时间序列。构建了一个数学模型，该模型模拟了甲苯磺丁脲在肝脏切片中的摄取及其代谢。此外，该模型还考虑了甲苯磺丁脲与细胞成分的结合以及在水相和脂质相中的分配。模型分析要求对切片中的母体化合物以及从切片和介质中收集的代谢物进行采样。将模型校准至数据，拟合固有清除率、肝脏材料中母体化合物的游离分数以及描述甲苯磺丁脲介质 - 切片交换的扩散参数。此外，为确保理论模型的有意义应用，在实验前和实验期间监测切片活力参数。对于不同的孵育，在不校正切片活力时，每单位体积切片的固有清除率范围为0.035至0.086 min⁻¹，在校正切片活力时为0.044至0.11 min⁻¹。将结果外推至大鼠甲苯磺丁脲的PBPK模型。通过将PBPK模型校准至先前的体内数据得到的固有清除率值为0.090 min⁻¹。该结果表明肝脏切片是预测低摄取化合物体内固有清除率的有价值工具。
