Abstract

Intestinal CYP3A and P-glycoprotein (P-gp) decrease the intestinal absorption of substrate drugs. Since substrate specificity of CYP3A often overlaps that of P-gp, and estimation of their saturability in the intestine is difficult, dose-dependent F_aF_g (fraction of the administered drugs that reach the portal blood) of substrate drugs and the relative importance of CYP3A and P-gp have not been clarified in many cases. Thus, we tried to establish the universal methodology for predicting the in vivo absorption of several CYP3A and/or P-gp substrates from in vitro assays. One of the key points is to set up the scaling factor (SF), correcting the difference between the observed in vivo clearance and the predicted clearance from in vitro data. The SFs of V_max for CYP3A (SF_CYP3A) and P-gp (SF_P-gp) were simultaneously optimized to explain the F_aF_g of CYP3A and/or P-gp substrate drugs. The best predictability of F_aF_g was achieved when considering both SF_CYP3A and SF_P-gp. The simulation also clarified the relative importance of CYP3A and P-gp in determining F_aF_g. In particular, the nonlinear intestinal absorption of verapamil was caused by the saturation of intestinal CYP3A, whereas that of quinidine was governed by the saturation of both CYP3A and P-gp. In addition, the dose-dependent F_aF_g of selective and dual CYP3A and/or P-gp substrates was well predicted. We therefore propose a methodology for predicting the F_aF_g of drugs using a mathematical model with optimized SF_CYP3A and SF_P-gp. Our methodology is applicable to in vitro–in vivo extrapolation of intestinal absorption, even if absolute in vivo functions of enzymes/transporters are unclear.