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Effect of ABCC2 (MRP2) Transport Function on Erythromycin Metabolism
- Source :
- Clinical Pharmacology & Therapeutics, 89(5), 693-701. Wiley-Blackwell
- Publication Year :
- 2011
- Publisher :
- Springer Science and Business Media LLC, 2011.
-
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.
- Subjects :
- Adult
Male
medicine.medical_specialty
CYP3A
Midazolam
Erythromycin
Pharmacology
Article
Cell Line
Cohort Studies
Mice
Young Adult
Dogs
Internal medicine
Cytochrome P-450 CYP3A
medicine
Animals
Humans
Pharmacology (medical)
Aged
Antibacterial agent
Mice, Knockout
CYP3A4
biology
Multidrug resistance-associated protein 2
Homozygote
Genetic Variation
Cytochrome P450
Middle Aged
Multidrug Resistance-Associated Protein 2
Protein Transport
Endocrinology
biology.protein
Female
Multidrug Resistance-Associated Proteins
Drug metabolism
medicine.drug
Subjects
Details
- ISSN :
- 15326535 and 00099236
- Volume :
- 89
- Database :
- OpenAIRE
- Journal :
- Clinical Pharmacology & Therapeutics
- Accession number :
- edsair.doi.dedup.....f7b45ea53c82afc7da7f4592e14f4dbe