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Intestinal transporter- and biliary excretion- mediated food effect


About this webinar

Food intake may alter the function of intestinal drug transporters. After a high-fat meal, the pH in human jejunum decreases from 6.8 under fasted state to approximately 6 and the total concentration of bile salts in jejunum increased from 3 mM to 10 mM. In a literature-based study, we assessed the effects of postprandial changes in human jejunal bile salt concentrations and pH on the function of drug transporters expressed on the apical side of enterocytes. It was found that based on in vitro inhibition IC50 values of bile acids on transporters, BCRP, MRP2, OATP2B1, ASBT, and MCT1 are likely to be inhibited by bile salts underfed state. Meanwhile, in vitro pH-dependent drug uptake or efflux assays showed that when the pH of the apical medium is adjusted from 6.8 to 6.0, the uptake or efflux of BCRP, PEPT1, OATP2B1, MCT1 substrates increases while the uptake of OCT3 and OCTN1/2 substrates decreases. P-gp mediated efflux is unlikely to be affected by postprandial changes in bile salts concentrations or pH. In addition, correlation analyses between food effect (changes in AUC underfed state) and the fraction of transporter-mediated drug uptake revealed that OATP2B1 inhibition by bile salts could contribute to the decreased oral absorption of OATP2B1 substrates underfed state while pH-enhanced PEPT1 uptake could contribute to the effect of food on PEPT1 substrates.

Many orally administered drugs with negative food effects (i.e. lower exposure under fed conditions) are often primarily or partially eliminated by biliary excretion. Through correlation analysis, we established a correlation between fed-state biliary clearance (CLb,fed) and fasted-state biliary clearance (CLb,fast) (y = 1.58*x, R2=0.77). The 1.6-fold increase in biliary clearance was then used as a correction factor to improve physiologically based pharmacokinetic (PBPK) prediction of food effect for five test drugs. The study suggests that the elimination of biliary excreted drugs is increased by food-stimulated bile flow, resulting in a decreased AUC underfed state compared to a fasting state.

The effects of bile salts and pH change on intestinal apical transporters and the increased biliary clearance underfed state can be incorporated into PBPK models to improve the predictions of food effects.

Learning Objectives

  • Describe the potential mechanisms of intestinal transporter-mediated food effect
  • Identify food intake-stimulated biliary clearance of some drugs, which partially explain the decreased drug exposure underfed state.
  • Discuss how to incorporate the postprandial changes in human jejunal bile salt concentrations and pH as well as biliary clearance into PBPK models to improve the prediction of food effects.

Moderated by Fuyuan Wang

May 7, 2020
Thu 12:30 PM EDT

Duration 1H 30M

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