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Research ArticleArticle

The Prediction of the Relative Importance of CYP3A/P-glycoprotein to the Nonlinear Intestinal Absorption of Drugs by Advanced Compartmental Absorption and Transit Model

Junichi Takano, Kazuya Maeda, Michael B. Bolger and Yuichi Sugiyama
Drug Metabolism and Disposition November 2016, 44 (11) 1808-1818; DOI: https://doi.org/10.1124/dmd.116.070011
Junichi Takano
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.)
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Kazuya Maeda
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.)
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Michael B. Bolger
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.)
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Yuichi Sugiyama
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.)
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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 Vmax for CYP3A (SFCYP3A) and P-gp (SFP-gp) were simultaneously optimized to explain the FaFg of CYP3A and/or P-gp substrate drugs. The best predictability of FaFg was achieved when considering both SFCYP3A and SFP-gp. The simulation also clarified the relative importance of CYP3A and P-gp in determining FaFg. 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 FaFg of selective and dual CYP3A and/or P-gp substrates was well predicted. We therefore propose a methodology for predicting the FaFg of drugs using a mathematical model with optimized SFCYP3A and SFP-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.

Footnotes

    • Received February 10, 2016.
    • Accepted August 17, 2016.
  • J.T. and K.M. equally contributed to this work.

  • This study was supported in part by a Grant-in-Aid for Young Scientists (A) [Grant 24689009] from the Ministry of Education, Culture, Sports, Science and Technology (to K.M.).

  • dx.doi.org/10.1124/dmd.116.070011.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (11)
Drug Metabolism and Disposition
Vol. 44, Issue 11
1 Nov 2016
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Research ArticleArticle

Predictive Model for Nonlinear Intestinal Absorption

Junichi Takano, Kazuya Maeda, Michael B. Bolger and Yuichi Sugiyama
Drug Metabolism and Disposition November 1, 2016, 44 (11) 1808-1818; DOI: https://doi.org/10.1124/dmd.116.070011

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Research ArticleArticle

Predictive Model for Nonlinear Intestinal Absorption

Junichi Takano, Kazuya Maeda, Michael B. Bolger and Yuichi Sugiyama
Drug Metabolism and Disposition November 1, 2016, 44 (11) 1808-1818; DOI: https://doi.org/10.1124/dmd.116.070011
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