TY - JOUR T1 - Fraction Unbound for Liver Microsome and Hepatocyte Incubations for All Major Species Can Be Approximated Using a Single-Species Surrogate JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 419 LP - 423 DO - 10.1124/dmd.118.085936 VL - 47 IS - 4 AU - John T. Barr AU - Julie M. Lade AU - Thuy B. Tran AU - Upendra P. Dahal Y1 - 2019/04/01 UR - http://dmd.aspetjournals.org/content/47/4/419.abstract N2 - 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. ER -