@article {Riccardidmd.117.079152, author = {Keith A Riccardi and Sangwoo Ryu and Jian Lin and Phillip Yates and David A Tess and Rui Li and Dhirender Singh and Brian R. Holder and Brendon Kapinos and George Chang and Li Di}, title = {Comparison of Species and Cell-Type Differences in Fraction Unbound of Liver Tissues, Hepatocytes and Cell-Lines}, elocation-id = {dmd.117.079152}, year = {2018}, doi = {10.1124/dmd.117.079152}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {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 HEK-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 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, 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 (i.e., fu,inc) 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.}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/early/2018/02/02/dmd.117.079152}, eprint = {https://dmd.aspetjournals.org/content/early/2018/02/02/dmd.117.079152.full.pdf}, journal = {Drug Metabolism and Disposition} }