The main objective was to evaluate and propose methods for predicting biliary clearance (CL(bile)) and enterohepatic circulation (EHC) of intact drugs in man. Another aim was to evaluate to role of intestinal drug secretion and propose a method for prediction of intestinal secretion CL (CL(i)). Animal data poorly predict the CL and CL(bile) of biliary excreted drugs, and the suggested molecular weight threshold for bile excretion as the dominant elimination route does not seem to hold. Active transport, low metabolic intrinsic CL (CL(int)) and, as an approximation, permeability (P(e)) less than that of metoprolol is required for substantial CL(bile) to occur. The typical EHC plasma concentration vs time profile (multiple peaks) is demonstrated for many low metabolic CL(int)-compounds with efflux and moderate to high intestinal P(e) and fraction absorbed. Physiologically-based in-vitro to in-vivo (PB-IVIV) methodology with in-vitro intrinsic CL(bile)-data obtained with sandwich-cultured human hepatocytes has generated 2- and 5-fold underpredictions for two compounds with intermediate to high CL(bile). This is despite not considering the unbound fraction. Possible explanations include low transporter activity and diffusion limitations in the in-vitro experiments. Intestinal reabsorption and EHC were also neglected in these predictions and in-vivo CL(bile) estimations. The sandwich model and these reference data are still very useful. Consideration of an empirical scaling factor and a newly developed approach that accounts for intestinal reabsorption and EHC could potentially lead to improved PB-IVIV predictions of CL(bile). Apparently, no attempts have been made to predict CL(i). Elimination via the intestinal route does not appear to be of great importance for the few compounds with available data, but could be equally as important as bile excretion. Net secretion in-vitro P(e) and newly estimated in-vivo intrinsic CL(i) data for digoxin and rosuvastatin could be useful for approximation of CL(i) of other compounds.