PT  - JOURNAL ARTICLE
AU  - Koen van de Wetering
AU  - Noam Zelcer
AU  - Annemieke Kuil
AU  - Wouter Feddema
AU  - Michel Hillebrand
AU  - Maria L. H. Vlaming
AU  - Alfred H. Schinkel
AU  - Jos H. Beijnen
AU  - Piet Borst
TI  - Multidrug Resistance Proteins 2 and 3 Provide Alternative Routes for Hepatic Excretion of Morphine-Glucuronides
AID  - 10.1124/mol.107.035592
DP  - 2007 Aug 01
TA  - Molecular Pharmacology
PG  - 387--394
VI  - 72
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/72/2/387.short
4100  - http://molpharm.aspetjournals.org/content/72/2/387.full
SO  - Mol Pharmacol2007 Aug 01; 72
AB  - Glucuronidation is a major hepatic detoxification pathway for endogenous and exogenous compounds, resulting in the intracellular formation of polar metabolites that require specialized transporters for elimination. Multidrug resistance proteins (MRPs) are expressed in the liver and can transport glucuronosyl-conjugates. Using morphine as a model aglycone, we demonstrate that morphine-3-glucuronide (M3G), the predominant metabolite, is transported in vitro by human MRP2 (ABCC2), a protein present in the apical membrane of hepatocytes. Loss of biliary M3G secretion in Mrp2(-/-) mice results in its increased sinusoidal transport that can be attributed to Mrp3. Combined loss of Mrp2 and Mrp3 leads to a substantial accumulation of M3G in the liver, from which it is transported across the sinusoidal membrane at a low rate, resulting in the prolonged presence of M3G in plasma. Our results show that murine Mrp2 and Mrp3 provide alternative routes for the excretion of a glucuronidated substrate from the liver in vivo.