Potential role of intestinal first-pass metabolism in the prediction of drug-drug interactions

Expert Opin Drug Metab Toxicol. 2008 Jul;4(7):909-22. doi: 10.1517/17425255.4.7.909.


Background: The contribution of intestine to the magnitude of drug-drug interactions (DDI) may be significant, considering high levels of inhibitors in the gut lumen achieved during absorption and the abundance of metabolic enzymes in the mature enterocytes. Intestinal inhibition is incorporated in the DDI prediction models as the ratio of the intestinal wall availability in the presence and absence of the inhibitor (F(G)(') and F(G), respectively).

Objective: This review will focus on the ability of the current approaches to estimate the extent of intestinal DDI accurately, addressing predominantly the most abundant intestinal P450 enzyme, CYP3A4.

Methods: Considering the sensitivity of the DDI prediction models to the accuracy of the F(G) estimates, the current study focuses on 3 different in vitro and in vivo approaches to assess this parameter.

Results/conclusion: The advantages and limitations of each of F(G) methods are outlined. Accurate assessment of this parameter is essential for the prediction of human drug clearance and drug-drug interaction potential.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cytochrome P-450 Enzyme System / metabolism
  • Drug Interactions*
  • Food-Drug Interactions
  • Humans
  • Intestinal Mucosa / metabolism*
  • Intestines / enzymology
  • Pharmaceutical Preparations / metabolism*
  • Pharmacokinetics


  • Pharmaceutical Preparations
  • Cytochrome P-450 Enzyme System