Physiologically Based Pharmacokinetic Modeling of Intestinal First-Pass Metabolism of CYP3A Substrates with High Intestinal Extraction

Abstract

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 F(G) 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 model-dependent. 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%).