@article {Barr419, author = {Barr, John T. and Lade, Julie M. and Tran, Thuy B. and Dahal, Upendra P.}, title = {Fraction Unbound for Liver Microsome and Hepatocyte Incubations for All Major Species Can Be Approximated Using a Single-Species Surrogate}, volume = {47}, number = {4}, pages = {419--423}, year = {2019}, doi = {10.1124/dmd.118.085936}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {It is well recognized that nonspecific binding of a drug within an in vitro assay (fu) can have a large impact on in vitro to in vivo correlations of intrinsic clearance. Typically, this value is determined experimentally across multiple species in the drug-discovery stage. Herein we examine the feasibility of using a single species (rat) as a surrogate for other species using a panel of small molecules representing highly diverse structures and physiochemical classes. The study demonstrated that 86\% and 92\% of the tested compounds measured in the mouse, dog, monkey, and human were within 2-fold of rat values for fu in microsomes and hepatocytes, respectively. One compound, amiodarone, exhibited unique species-dependent binding where the fu was approximately 10-fold higher in human microsomes and 20-fold higher in human hepatocytes compared with the average of the other species tested. Overall, these data indicate that using a single species (rat) fu as a surrogate for other major species, including humans, is a means to increase the throughput of measuring nonspecific binding in vitro.}, issn = {0090-9556}, URL = {http://dmd.aspetjournals.org/content/47/4/419}, eprint = {http://dmd.aspetjournals.org/content/47/4/419.full.pdf}, journal = {Drug Metabolism and Disposition} }