Abstract

The aim of this study was to evaluate a unified method for predicting human in vivo intrinsic clearance (CL_{int, in vivo}) and hepatic clearance (CL_h) from in vitro data in hepatocytes and microsomes by applying the unbound fraction in blood (fu_b) and in vitro incubations (fu_inc). Human CL_{int, in vivo} was projected using in vitro data together with biological scaling factors and compared with the unbound intrinsic clearance (CL_{int, ub, in vivo}) estimated from clinical data using liver models with and without the various fu terms. For incubations conducted with fetal calf serum (n = 14), the observed CL_{int, in vivo} was modeled well assuming fu_inc and fu_b were equivalent. CL_{int, ub, in vivo} was predicted best using both fu_b and fu_inc for other hepatocyte data (n = 56; r² = 0.78, p = 3.3 × 10^–19, average fold error = 5.2). A similar model for CL_{int, ub, in vivo} was established for microsomal data (n = 37; r² = 0.77, p = 1.2 × 10^–12, average fold error = 6.1). Using the model for CL_{int, ub, in vivo} (including a further empirical scaling factor), the CL_h in humans was also calculated according to the well stirred liver model for the most extensive dataset. CL_{int, in vivo} and CL_h were both predicted well using in vitro human data from several laboratories for acidic, basic, and neutral drugs. The direct use of this model using only in vitro human data to predict the metabolic component of CL_h is attractive, as it does not require extra information from preclinical studies in animals.