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The unbound partition coefficient (Kp uu ) allows the estimation of intracellular target exposure from free extracellular drug concentrations. Although the active mechanisms controlling Kp uu are saturable, Kp uu is commonly determined at a single concentration, which may not be appropriate in cases in which drug concentrations can largely vary, e.g., in plasma in vivo or in vitro IC 50 assays. We examined the concentration dependence of Kp uu in vitro using KAT6A inhibitors with varying potency drop-off in ZR75-1 breast cancer cells to account for exposure-related discrepancies between cellular and biochemical IC 50 Considering saturability resulted in a better quantitative bridge between both IC 50 values and gave way to a simplified method to determine Kp uu that is suitable for the prediction of unbound cytosolic drug concentrations without the need to generate f u,cell estimates from binding studies in cell homogenates. As opposed to the binding method, which destroys cellular integrity, this approach provides an alternative f u,cell estimate and directly reflects the fraction of unbound drug in the cell cytosol based on Kp saturation (f u,cyto ) of intact cells. In contrast to the binding method, prediction of intracellular KAT6A exposure with this more physiologic approach was able to bridge the average exposure gap between biochemical and cellular IC 50 values from 73-fold down to only 5.4-fold. The concept of concentration-dependent Kp uu provides a solid rationale for early drug discovery to discriminate between pharmacology and target exposure-related IC 50 discrepancies. The attractiveness of the approach also lies in the use of the same assay format for cellular IC 50 , f u,cyto , and the unbound partition coefficient based on f u,cyto (Kp uu,cyto ) determination. SIGNIFICANCE STATEMENT: Examination of the yet-unexplored concentration dependence of the unbound partition coefficient led to a new experimental approach that resulted in more reliable predictions of intracellular target exposure and is well suited for routine drug discovery projects.

drug metabolism and disposition/dmd online

Concentration Dependence of the Unbound Partition Coefficient Kp<sub>uu</sub> and Its Application to Correct for Exposure-Related Discrepancies between Biochemical and Cellular Potency of KAT6A Inhibitors

Concentration Dependence of the Unbound Partition Coefficient Kpuu and Its Application to Correct for Exposure-Related Discrepancies between Biochemical and Cellular Potency of KAT6A Inhibitors

Concentration Dependence of the Unbound Partition Coefficient Kp_uu and Its Application to Correct for Exposure-Related Discrepancies between Biochemical and Cellular Potency of KAT6A Inhibitors