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First published on May 7, 2007; DOI: 10.1124/mol.107.035592

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Received for publication March 1, 2007.
Revised April 10, 2007.
Accepted for publication May 7, 2007.

Multidrug resistance protein 2 and 3 provide alternative routes for hepatic excretion of morphine-glucuronides

Koen van de Wetering 1, Noam Zelcer 1, Annemieke Kuil 1, Wouter Feddema 1, Michel Hillebrand 2, Maria L. H. Vlaming 1, Alfred H. Schinkel 1, Jos H. Beijnen 2, Piet Borst 3*

1 The Netherlands Cancer Institute 2 Slotervaart Hospital 3 Netherlands Cancer Institute

* Address correspondence to: E-mail: p.borst{at}nki.nl

Abstract

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.


Key words: Opioid, Organic anion, Liver transporters, Phase II enzymes, UDP-glucuronyltransferases, Opioids


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