Loss in potency is commonly observed in early drug discovery when moving from biochemical to more complex cellular systems. Among other factors, low permeability is often considered to cause such potency disconnects. We developed a novel cellular disposition assay in MDCK cells to determine passive uptake clearance (PS inf ), cell-to-medium ratios at steady-state (K p ) and the time to reach 90% steady-state (TTSS 90 ) from a single experiment in a high-throughput format. The assay was validated using 40 marketed drugs, showing a wide distribution of PS inf and K p values. The parameters generally correlated with transcellular permeability and lipophilicity, while PS inf data revealed better resolution in the high and low permeability ranges compared to traditional permeability data. A linear relationship between the K p /PS inf ratio and TTSS 90 was mathematically derived and experimentally validated, demonstrating the dependency of TTSS 90 on the rate and extent of cellular accumulation. Cellular disposition parameters could explain potency (IC 50 ) disconnects noted for seven Bruton's tyrosine kinase degrader compounds in a cellular potency assay. In contrast to transcellular permeability, PS inf data enabled identification of the compounds with IC 50 disconnects based on their time to reach equilibrium. Overall, the novel assay offers the possibility to address potency disconnects in early drug discovery.