Disposition of naringenin via glucuronidation pathway is affected by compensating efflux transporters of hydrophilic glucuronides

Mol Pharm. Nov-Dec 2009;6(6):1703-15. doi: 10.1021/mp900013d.


The purposes of this study were to investigate how efflux transporters and UDP-glucuronosyltransferases (UGT) affect the disposition of naringenin. A rat intestinal perfusion model with bile duct cannulation was used along with rat intestinal and liver microsomes. In the intestinal perfusion model, both absorption and subsequent excretion of naringenin metabolites were rapid and site-dependent (p < 0.05). Naringenin was absorbed the most in colon, and its glucuronides were excreted the most in duodenum. In metabolism studies, the intrinsic clearance value of naringenin glucuronidation was the highest in jejunum microsomes, followed by liver, ileal and colonic microsomes. The rapid metabolism in microsomes did not always translate into more efficient excretion in the rat perfusion model, however, because of presence of rate-limiting efflux transporters. When used separately, MK-571 (an inhibitor of multidrug resistance-related protein 2 or Mrp2) or dipyridamole (an inhibitor of breast cancer resistance protein or Bcrp1) did not affect excretion of naringenin glucuronides, but when used together, they significantly (p < 0.05) decreased intestinal and biliary excretion of naringenin glucuronides. In conclusion, efflux transporters Mrp2 and Bcrp1 are shown to compensate for each other and enable the intestinal excretion of flavonoid (i.e., naringenin) glucuronides.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / antagonists & inhibitors
  • ATP-Binding Cassette Transporters / metabolism
  • Animals
  • Biological Transport / drug effects
  • Chromatography, High Pressure Liquid
  • Dipyridamole / pharmacology
  • Flavanones / blood
  • Flavanones / metabolism*
  • Glucuronides / blood
  • Glucuronides / metabolism*
  • Intestinal Mucosa / metabolism*
  • Intestines / drug effects
  • Leukotriene Antagonists / pharmacology
  • Liver / drug effects
  • Liver / metabolism*
  • Male
  • Microsomes / drug effects
  • Microsomes / metabolism*
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism*
  • Models, Biological
  • Models, Theoretical
  • Multidrug Resistance-Associated Proteins / antagonists & inhibitors
  • Multidrug Resistance-Associated Proteins / metabolism
  • Phosphodiesterase Inhibitors / pharmacology
  • Propionates / pharmacology
  • Quinolines / pharmacology
  • Rats
  • Rats, Wistar
  • Tandem Mass Spectrometry


  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Abcg2 protein, rat
  • Flavanones
  • Glucuronides
  • Leukotriene Antagonists
  • Multidrug Resistance-Associated Proteins
  • Phosphodiesterase Inhibitors
  • Propionates
  • Quinolines
  • multidrug resistance-associated protein 2
  • verlukast
  • Dipyridamole
  • naringenin