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...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2005-05, Vol.102 (20), p.7274-7279 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Zelcer, Noam van de Wetering, Koen Hillebrand, Michel Sarton, Elise Kuil, Annemieke Wielinga, Peter R. Tephly, Thomas Dahan, Albert Beijnen, Jos H. Borst, Piet |
| description | 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. |
| doi_str_mv | 10.1073/pnas.0502530102 |
| format | Article |
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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.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.0502530102</identifier><identifier>PMID: 15886284</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animals ; ATP Binding Cassette Transporter, Sub-Family B - deficiency ; ATP Binding Cassette Transporter, Sub-Family B - metabolism ; ATP binding cassette transporters ; ATP-Binding Cassette Transporters - metabolism ; Bile ; Bile - metabolism ; Biological Sciences ; Cell Line ; Dosage ; Drug resistance ; Excretion ; Glucuronosyltransferase ; Hepatocytes ; Humans ; Liver ; Liver - metabolism ; Mice ; Mice, Knockout ; Morphine ; Morphine - pharmacokinetics ; Morphine Derivatives - blood ; Morphine Derivatives - metabolism ; Morphine Derivatives - pharmacokinetics ; Morphine Derivatives - pharmacology ; Narcotics ; Pain Measurement - drug effects ; Pharmacokinetics ; Pharmacology ; Protein Transport ; Proteins ; Reaction kinetics ; Rodents ; Spodoptera ; Tissue Distribution ; Transport Vesicles - metabolism ; Urine</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2005-05, Vol.102 (20), p.7274-7279</ispartof><rights>Copyright 1993/2005 The National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences May 17, 2005</rights><rights>Copyright © 2005, The National Academy of Sciences 2005</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c588t-116032d637483ec8cb41638a8128d2ebea4c09b7df8d4792da64e0d79e08a6c53</citedby><cites>FETCH-LOGICAL-c588t-116032d637483ec8cb41638a8128d2ebea4c09b7df8d4792da64e0d79e08a6c53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/102/20.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/3375521$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/3375521$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27924,27925,53791,53793,58017,58250</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15886284$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zelcer, Noam</creatorcontrib><creatorcontrib>van de Wetering, Koen</creatorcontrib><creatorcontrib>Hillebrand, Michel</creatorcontrib><creatorcontrib>Sarton, Elise</creatorcontrib><creatorcontrib>Kuil, Annemieke</creatorcontrib><creatorcontrib>Wielinga, Peter R.</creatorcontrib><creatorcontrib>Tephly, Thomas</creatorcontrib><creatorcontrib>Dahan, Albert</creatorcontrib><creatorcontrib>Beijnen, Jos H.</creatorcontrib><creatorcontrib>Borst, Piet</creatorcontrib><title>Mice Lacking Multidrug Resistance Protein 3 Show Altered Morphine Pharmacokinetics and Morphine-6-Glucuronide Antinociception</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>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. 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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. 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| subjects | Animals ATP Binding Cassette Transporter, Sub-Family B - deficiency ATP Binding Cassette Transporter, Sub-Family B - metabolism ATP binding cassette transporters ATP-Binding Cassette Transporters - metabolism Bile Bile - metabolism Biological Sciences Cell Line Dosage Drug resistance Excretion Glucuronosyltransferase Hepatocytes Humans Liver Liver - metabolism Mice Mice, Knockout Morphine Morphine - pharmacokinetics Morphine Derivatives - blood Morphine Derivatives - metabolism Morphine Derivatives - pharmacokinetics Morphine Derivatives - pharmacology Narcotics Pain Measurement - drug effects Pharmacokinetics Pharmacology Protein Transport Proteins Reaction kinetics Rodents Spodoptera Tissue Distribution Transport Vesicles - metabolism Urine |
| title | Mice Lacking Multidrug Resistance Protein 3 Show Altered Morphine Pharmacokinetics and Morphine-6-Glucuronide Antinociception |
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