Centre for Applied Pharmacokinetic Research, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PT, UK.
Drug Metab Dispos. 2011 Sep;39(9):1633-42. doi: 10.1124/dmd.111.039248. Epub 2011 Jun 1.
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%).
肠腔可用度（F(G)）的预测对于评估口服清除率和药物相互作用的风险，以及药物在体内的处置具有重要意义。在本研究中，利用体外渗透性和清除率数据，在基于生理学的药代动力学（PBPK）模型中进行了 F(G)预测。并将预测成功率与 Q(Gut)模型进行了比较。此外，还将使用 PBPK 模型预测的表观口服清除率与荟萃分析的体内观察结果进行了比较。最后，在 8 个人类空肠微粒体（HJM）样本中测定了 12 种 CYP3A 底物的游离内在清除率（CLu(int)），以评估肠道内在清除率的个体间差异以及随后的 F(G)预测。总体而言，与 Q(Gut)模型相比，PBPK 模型改善了 F(G)的预测，这表现为偏差减小和精度提高。特别是，在预测茚地那韦、沙奎那韦和特非那定的 F(G)时，模型依赖性显著。所研究药物的预测口服清除率范围从他克莫司的 8.79 到 6320 l/h ，辛伐他汀分别为 17 到 14000 μl · min(-1) · mg(-1) ，除了茚地那韦、阿托伐他汀和丁螺环酮，预测值与观察值的比例在 3 倍以内。相应的 CLu(int) 估计的个体间变异性范围从阿托伐他汀的 41%到 67% ，沙奎那韦分别为 41%到 67% 。这些体外数据导致辛伐他汀和茚地那韦的预测 F(G)值分别在 0.03 到 0.94 之间。特非那定（65%）的个体间变异性最大，而茚地那韦（3%）的变异性则较低。
