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Analogous to the fraction unbound in microsomes (fu_mic), fraction unbound in hepatocyte incubations (fu_hep) is an important parameter in the prediction of intrinsic clearance and potential drug-drug interactions. A recent study by Austin et al. (Drug Metab Dispos 33:419–425, 2005) proposed a linear 1:1 relationship between the extent of binding to microsomes at 1 mg/ml and to hepatocytes at 10⁶ million cells/ml. The current study collates a fu_mic and fu_hep database for 39 drugs to examine the relationship between binding in microsomes and hepatocytes. A new nonlinear empirical equation is proposed as an alternative to the linear relationship to relate binding between the two systems. The nonlinear equation results in higher prediction accuracy and lower bias in comparison to the linear relationship, in particular for drugs with fu_hep < 0.4. The proposed equation is further extended to allow direct prediction of fu …