Effect of ABCC2 (MRP2) transport function on erythromycin metabolism

Clin Pharmacol Ther. 2011 May;89(5):693-701. doi: 10.1038/clpt.2011.25. Epub 2011 Mar 30.

Abstract

The macrolide antiobiotic erythromycin undergoes extensive hepatic metabolism and is commonly used as a probe for cytochrome P450 (CYP) 3A4 activity. By means of a transporter screen, erythromycin was identified as a substrate for the transporter ABCC2 (MRP2) and its murine ortholog, Abcc2. Because these proteins are highly expressed on the biliary surface of hepatocytes, we hypothesized that impaired Abcc2 function may influence the rate of hepatobiliary excretion and thereby enhance erythromycin metabolism. Using Abcc2 knockout mice, we found that Abcc2 deficiency was associated with a significant increase in erythromycin metabolism, whereas murine Cyp3a protein expression and microsomal Cyp3a activity were not affected. Next, in a cohort of 108 human subjects, we observed that homozygosity for a common reduced-function variant in ABCC2 (rs717620) was also linked to an increase in erythromycin metabolism but was not correlated with the clearance of midazolam. These results suggest that impaired ABCC2 function can alter erythromycin metabolism, independent of changes in CYP3A4 activity.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Cell Line
  • Cohort Studies
  • Cytochrome P-450 CYP3A / genetics
  • Cytochrome P-450 CYP3A / metabolism
  • Dogs
  • Erythromycin / metabolism*
  • Female
  • Genetic Variation / drug effects
  • Genetic Variation / physiology
  • Homozygote
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Midazolam / pharmacology
  • Middle Aged
  • Multidrug Resistance-Associated Proteins / deficiency
  • Multidrug Resistance-Associated Proteins / genetics
  • Multidrug Resistance-Associated Proteins / physiology*
  • Protein Transport / drug effects
  • Protein Transport / genetics
  • Young Adult

Substances

  • Multidrug Resistance-Associated Proteins
  • multidrug resistance-associated protein 2
  • Erythromycin
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Midazolam