Prediction of intestinal availability (F G), in conjunction with hepatic metabolism, is of considerable importance in drug disposition to assess oral clearance and liability to drug-drug interactions. In the current study, F G predictions were performed within a physiologically based pharmacokinetic (PBPK) model using in vitro permeability and clearance data. The prediction success was assessed in comparison with the Q Gut model. In addition, apparent oral clearance values, predicted using the PBPK model, were compared with in vivo observations from meta-analyses. Finally, unbound intrinsic clearance values (CLu int) were determined for 12 CYP3A substrates in eight individual human jejunal microsome (HJM) samples to assess interindividual variability in intestinal intrinsic clearance and subsequent F G predictions. Overall, the PBPK model improved FG predictions in comparison with the Q Gut model; this was apparent by a reduced bias and increased precision. In particular, F G predictions of indinavir, saquinavir, and terfenadine were modeldependent. The predicted oral clearance values of the drugs investigated ranged from 8.79 to 6320 l/h for tacrolimus and simvastatin, respectively, and were overall within 3-fold of the observed data with the exception of indinavir, atorvastatin, and buspirone. The individual HJM CLu int values ranged from 17 to 14,000 μl·min -1·mg -1 for atorvastatin and saquinavir, respectively, and corresponding interindividual variability in CLu int estimates ranged from 41 to 67%. These in vitro data resulted in predicted F G values ranging from 0.03 to 0.94 for simvastatin and indinavir, respectively. The largest interindividual variability of F G was predicted for terfenadine (65%) in contrast with the low variability in the case of indinavir (3%). Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics.