PT - JOURNAL ARTICLE AU - Michael Gertz AU - J. Brian Houston AU - Aleksandra Galetin TI - Physiologically-based pharmacokinetic modeling of intestinal first-pass metabolism of CYP3A substrates with high intestinal extraction AID - 10.1124/dmd.111.039248 DP - 2011 Jan 01 TA - Drug Metabolism and Disposition PG - dmd.111.039248 4099 - http://dmd.aspetjournals.org/content/early/2011/06/01/dmd.111.039248.short 4100 - http://dmd.aspetjournals.org/content/early/2011/06/01/dmd.111.039248.full AB - Prediction of intestinal availability (FG), in conjunction with hepatic metabolism, is of considerable importance in drug disposition in order to assess oral clearance and liability to drug-drug interactions. In the current study, FG predictions were performed using a physiologically-based pharmacokinetic (PBPK) model utilizing in vitro permeability and clearance data. The prediction success was assessed in comparison to the QGut model. In addition, apparent oral clearance, predicted using the PBPK model, was compared to in vivo observations from meta-analyses. Lastly, unbound intrinsic clearance values (CLuint ) were determined for 12 CYP3A substrates in eight individual human jejunal microsomal samples (HJM) to assess inter-individual variability in intestinal intrinsic clearance and subsequent FG predictions. Overall, the PBPK model improved FG predictions in comparison to the QGut model; this was apparent by a reduced bias and increased precision. In particular, FG predictions of indinavir, saquinavir and terfenadine were model-dependent. The predicted oral clearance values of the drugs investigated ranged from 8.79 to 6,320 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 CLuint values ranged from 17 to 14,000 μ/min/mg for atorvastatin and saquinavir, respectively and corresponding inter-individual variability in CLuint estimates ranged from 41 to 67%. These in vitro data resulted in predicted FG values ranging from 0.03 to 0.94 for simvastatin and indinavir, respectively. The largest inter-individual variability of FG was predicted for terfenadine (65%) in contrast to the low variability in the case of indinavir (3%).