Comparison of Species and Cell-Type Differences in Fraction Unbound of Liver Tissues, Hepatocytes, and Cell Lines
Comparison of Species and Cell-Type Differences in Fraction Unbound of Liver Tissues, Hepatocytes, and Cell Lines
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肝组织、肝细胞和细胞系未结合部分的物种和细胞类型差异比较
DOI：
10.1124/dmd.117.079152
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发表时间：
2018
影响因子：
3.9
通讯作者：
L. Di
中科院分区：
文献类型：
--
作者：
K. Riccardi;Sangwoo Ryu;Jian Lin;P. Yates;D. Tess;Rui Li;Dhirender Singh;B. Holder;B. Kapinos;G. Chang;L. Di
肝组织、肝细胞和其他细胞类型的游离分数(FU)是估算肝细胞内游离药物浓度和细胞内游离药物浓度的重要参数。在药物发现和开发的各种应用中，FU、肝脏和FU，细胞经常被测量在多种物种和细胞类型中。用平衡透析法对5种不同物种(小鼠、大鼠、狗、猴、人)的肝细胞和人胚胎肾293细胞系和HuH7细胞系的FU、肝脏和FU的12个基质进行了比较研究，得到了22个结构不同的化合物。采用平均生物等效性方法，我们的结果表明，与肝组织、肝细胞或不同细胞类型结合的平均差异在大鼠肝脏的2倍以内。因此，我们建议在药物开发中使用大鼠肝脏作为其他物种和细胞类型肝脏结合的替代物。这一策略有可能简化结合研究并降低成本，从而能够更有效和实用地测定肝组织、肝细胞和其他细胞类型的FU。此外，肝细胞稳定孵育条件下的FU不应与FU细胞混淆，因为一个是稀释的FU，另一个是未稀释的FU。细胞密度对FU，细胞的准确测量也起着至关重要的作用。
Fraction unbound (fu) of liver tissue, hepatocytes, and other cell types is an essential parameter used to estimate unbound liver drug concentration and intracellular free drug concentration. fu,liver and fu,cell are frequently measured in multiple species and cell types in drug discovery and development for various applications. A comparison study of 12 matrices for fu,liver and fu,cell of hepatocytes in five different species (mouse, rat, dog, monkey, and human), as well as fu,cell of Huh7 and human embryonic kidney 293 cell lines, was conducted for 22 structurally diverse compounds with the equilibrium dialysis method. Using an average bioequivalence approach, our results show that the average difference in binding to liver tissue, hepatocytes, or different cell types was within 2-fold of that of the rat fu,liver. Therefore, we recommend using rat fu,liver as a surrogate for liver binding in other species and cell types in drug discovery. This strategy offers the potential to simplify binding studies and reduce cost, thereby enabling a more effective and practical determination of fu for liver tissues, hepatocytes, and other cell types. In addition, fu under hepatocyte stability incubation conditions should not be confused with fu,cell, as one is a diluted fu and the other is an undiluted fu. Cell density also plays a critical role in the accurate measurement of fu,cell.
用于肝脏支持的大鼠小肝细胞：培养物中的生长和代谢活动
DOI：
--
发表时间：
2002
期刊：
J Artif Organs 5
影响因子：
--
作者：
Kamachi H;et al.
通讯作者：
et al.