title: The Prediction of the Relative Importance of CYP3A/P-glycoprotein to the Nonlinear Intestinal Absorption of Drugs by Advanced Compartmental Absorption and Transit Model.
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 FaFg(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 Vmaxfor CYP3A (SFCYP3A) and P-gp (SFP-gp) were simultaneously optimized to explain the FaFgof CYP3A and/or P-gp substrate drugs. The best predictability of FaFgwas achieved when considering both SFCYP3Aand SFP-gpThe simulation also clarified the relative importance of CYP3A and P-gp in determining FaFgIn 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 FaFgof selective and dual CYP3A and/or P-gp substrates was well predicted. We therefore propose a methodology for predicting the FaFgof drugs using a mathematical model with optimized SFCYP3Aand SFP-gpOur methodology is applicable to in vitro-in vivo extrapolation of intestinal absorption, even if absolute in vivo functions of enzymes/transporters are unclear.
authors.affiliation: Kyorin Pharmaceutical Co., Ltd., Tokyo, Japan (J.T.); Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (K.M.); Simulations Plus, Inc., Lancaster, California (M.B.B.); and Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Cluster for Industry Partnerships, RIKEN, Kanagawa, Japan (Y.S.) junichi.takano@mb.kyorin-pharm.co.jp.
authors.forename: Junichi
authors.initials: J
authors.lastname: Takano
authors.affiliation: Kyorin Pharmaceutical Co., Ltd., Tokyo, Japan (J.T.); Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (K.M.); Simulations Plus, Inc., Lancaster, California (M.B.B.); and Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Cluster for Industry Partnerships, RIKEN, Kanagawa, Japan (Y.S.).
authors.forename: Kazuya
authors.initials: K
authors.lastname: Maeda
authors.affiliation: Kyorin Pharmaceutical Co., Ltd., Tokyo, Japan (J.T.); Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (K.M.); Simulations Plus, Inc., Lancaster, California (M.B.B.); and Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Cluster for Industry Partnerships, RIKEN, Kanagawa, Japan (Y.S.).
authors.forename: Michael B
authors.initials: MB
authors.lastname: Bolger
authors.affiliation: Kyorin Pharmaceutical Co., Ltd., Tokyo, Japan (J.T.); Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (K.M.); Simulations Plus, Inc., Lancaster, California (M.B.B.); and Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Cluster for Industry Partnerships, RIKEN, Kanagawa, Japan (Y.S.).
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D001682:Biological Availability; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007700:Kinetics; D008954:Models, Biological; D011802:Quinidine / Q000378:metabolism; D014700:Verapamil / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014700:Verapamil; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D011802:Quinidine