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Prediction of Nonlinear Intestinal Absorption of CYP3A4 and P-Glycoprotein Substrates from their In Vitro Km Values

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ABSTRACT

Purpose

CYP3A4 and P-glycoprotein (P-gp) are present in the human intestine and mediate intestinal first-pass metabolism and the efflux of oral drugs, respectively. We aimed to predict whether intestinal CYP3A4/P-gp is saturated in a therapeutic dose range.

Methods

Information on the Michaelis–Menten constant (Km), product of the fraction absorbed (Fa) and intestinal availability (Fg) (FaFg) of CYP3A4/P-gp substrates, and clinical AUC data including two or more different dosages for each CYP3A4/P-gp substrate was collected. The relationship between dose-normalized AUC and dose/Km value, termed the linearity index (LIN), was analyzed.

Results

Among 38 CYP3A4 and/or P-gp substrates, 16 substrates exhibited nonlinear pharmacokinetics and 22 substrates exhibited linear pharmacokinetics. Substrates with a small LIN tended to exhibit linear pharmacokinetics. The smallest LIN values of a substrate that exhibited nonlinear pharmacokinetics were 2.8 and 0.77 L for CYP3A4 and P-gp substrates, respectively. A decision tree for predicting nonlinear pharmacokinetics of CYP3A4/P-gp substrates based on LIN and FaFg of drugs was proposed. This decision tree correctly predicted linearity or nonlinearity for 24 of 29 drugs.

Conclusions

LIN is useful for predicting CYP3A4/P-gp-mediated nonlinearity in intestinal absorption process in humans.

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Author information

Authors and Affiliations

  1. Pre-clinical Research Department, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka, 412-8513, Japan

    Tatsuhiko Tachibana & Motohiro Kato

  2. Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

    Yuichi Sugiyama

Authors
  1. Tatsuhiko Tachibana
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  2. Motohiro Kato
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  3. Yuichi Sugiyama
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Corresponding author

Correspondence to Tatsuhiko Tachibana.

Appendix

Appendix

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Tachibana, T., Kato, M. & Sugiyama, Y. Prediction of Nonlinear Intestinal Absorption of CYP3A4 and P-Glycoprotein Substrates from their In Vitro Km Values. Pharm Res 29, 651–668 (2012). https://doi.org/10.1007/s11095-011-0579-2

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