Mice lacking multidrug resistance protein 3 show altered morphine pharmacokinetics and morphine-6-glucuronide antinociception.
Glucuronidation is a major detoxification pathway for endogenous and exogenous compounds in mammals that results in the intracellular formation of polar metabolites, requiring specialized transporters to cross biological membranes. By using morphine as a model aglycone, we demonstrate that multidrug resistance protein 3 (MRP3/ABCC3), a protein present in the basolateral membrane of polarized cells, transports morphine-3-glucuronide (M3G) and morphine-6-glucuronide in vitro. Mrp3(-/-) mice are unable to excrete M3G from the liver into the bloodstream, the major hepatic elimination route for this drug. This results in increased levels of M3G in liver and bile, a 50-fold reduction in the plasma levels of M3G, and in a major shift in the main disposition route for morphine and M3G, predominantly via the urine in WT mice but via the feces in Mrp3(-/-) mice. The pharamacokinetics of injected morphine-glucuronides are altered as well in the absence of Mrp3, and this results in a decreased antinociceptive potency of injected morphine-6-glucuronide.
Zelcer
Noam
N
Division of Molecular Biology and Center of Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
van de Wetering
Koen
K
Hillebrand
Michel
M
Sarton
Elise
E
Kuil
Annemieke
A
Wielinga
Peter R
PR
Tephly
Thomas
T
Dahan
Albert
A
Beijnen
Jos H
JH
Borst
Piet
P
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001646:Bile / Q000378:metabolism; D002460:Cell Line; D014453:Glucuronosyltransferase; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000493:pharmacokinetics*; D009022:Morphine Derivatives / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D021381:Protein Transport; D018411:Spodoptera; D014018:Tissue Distribution; D022161:Transport Vesicles / Q000378:metabolism
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D009022:Morphine Derivatives; C035349:morphine-6-glucuronide; D009020:Morphine; C095122:multidrug resistance protein 3; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; C018108:morphine-3-glucuronide