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Pharmaceutical Research

, Volume 29, Issue 3, pp 651–668 | Cite as

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

  • Tatsuhiko TachibanaEmail author
  • Motohiro Kato
  • Yuichi Sugiyama
Research Paper

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.

KEY WORDS

CYP3A4 human intestine nonlinear absorption P-gp 

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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Tatsuhiko Tachibana
    • 1
    Email author
  • Motohiro Kato
    • 1
  • Yuichi Sugiyama
    • 2
  1. 1.Pre-clinical Research DepartmentChugai Pharmaceutical Co., Ltd.GotembaJapan
  2. 2.Graduate School of Pharmaceutical SciencesThe University of TokyoBunkyo-kuJapan

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