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Research ArticleMetabolism, Transport, and Pharmacogenomics

Mechanistic Basis of Altered Morphine Disposition in Nonalcoholic Steatohepatitis

Anika L. Dzierlenga, John D. Clarke, Tiffanie L. Hargraves, Garrett R. Ainslie, Todd W. Vanderah, Mary F. Paine and Nathan J. Cherrington
Journal of Pharmacology and Experimental Therapeutics March 2015, 352 (3) 462-470; DOI: https://doi.org/10.1124/jpet.114.220764
Anika L. Dzierlenga
Departments of Pharmacology and Toxicology (A.L.D., J.D.C., T.L.H., N.J.C.) and Pharmacology (T.W.V.), University of Arizona, Tucson, Arizona; Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina (G.R.A., M.F.P.); and Section of Experimental and Systems Pharmacology, Washington State University, Spokane, Washington (G.R.A., M.F.P.)
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John D. Clarke
Departments of Pharmacology and Toxicology (A.L.D., J.D.C., T.L.H., N.J.C.) and Pharmacology (T.W.V.), University of Arizona, Tucson, Arizona; Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina (G.R.A., M.F.P.); and Section of Experimental and Systems Pharmacology, Washington State University, Spokane, Washington (G.R.A., M.F.P.)
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Tiffanie L. Hargraves
Departments of Pharmacology and Toxicology (A.L.D., J.D.C., T.L.H., N.J.C.) and Pharmacology (T.W.V.), University of Arizona, Tucson, Arizona; Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina (G.R.A., M.F.P.); and Section of Experimental and Systems Pharmacology, Washington State University, Spokane, Washington (G.R.A., M.F.P.)
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Garrett R. Ainslie
Departments of Pharmacology and Toxicology (A.L.D., J.D.C., T.L.H., N.J.C.) and Pharmacology (T.W.V.), University of Arizona, Tucson, Arizona; Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina (G.R.A., M.F.P.); and Section of Experimental and Systems Pharmacology, Washington State University, Spokane, Washington (G.R.A., M.F.P.)
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Todd W. Vanderah
Departments of Pharmacology and Toxicology (A.L.D., J.D.C., T.L.H., N.J.C.) and Pharmacology (T.W.V.), University of Arizona, Tucson, Arizona; Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina (G.R.A., M.F.P.); and Section of Experimental and Systems Pharmacology, Washington State University, Spokane, Washington (G.R.A., M.F.P.)
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Mary F. Paine
Departments of Pharmacology and Toxicology (A.L.D., J.D.C., T.L.H., N.J.C.) and Pharmacology (T.W.V.), University of Arizona, Tucson, Arizona; Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina (G.R.A., M.F.P.); and Section of Experimental and Systems Pharmacology, Washington State University, Spokane, Washington (G.R.A., M.F.P.)
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Nathan J. Cherrington
Departments of Pharmacology and Toxicology (A.L.D., J.D.C., T.L.H., N.J.C.) and Pharmacology (T.W.V.), University of Arizona, Tucson, Arizona; Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina (G.R.A., M.F.P.); and Section of Experimental and Systems Pharmacology, Washington State University, Spokane, Washington (G.R.A., M.F.P.)
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Abstract

Morphine is metabolized in humans to morphine-3-glucuronide (M3G) and the pharmacologically active morphine-6-glucuronide (M6G). The hepatobiliary disposition of both metabolites relies upon multidrug resistance-associated proteins Mrp3 and Mrp2, located on the sinusoidal and canalicular membrane, respectively. Nonalcoholic steatohepatitis (NASH), the severe stage of nonalcoholic fatty liver disease, alters xenobiotic metabolizing enzyme and transporter function. The purpose of this study was to determine whether NASH contributes to the large interindividual variability and postoperative adverse events associated with morphine therapy. Male Sprague-Dawley rats were fed a control diet or a methionine- and choline-deficient diet to induce NASH. Radiolabeled morphine (2.5 mg/kg, 30 µCi/kg) was administered intravenously, and plasma and bile (0–150 or 0–240 minutes), liver and kidney, and cumulative urine were analyzed for morphine and M3G. The antinociceptive response to M6G (5 mg/kg) was assessed (0–12 hours) after direct intraperitoneal administration since rats do not produce M6G. NASH caused a net decrease in morphine concentrations in the bile and plasma and a net increase in the M3G/morphine plasma area under the concentration-time curve ratio, consistent with upregulation of UDP-glucuronosyltransferase Ugt2b1. Despite increased systemic exposure to M3G, NASH resulted in decreased biliary excretion and hepatic accumulation of M3G. This shift toward systemic retention is consistent with the mislocalization of canalicular Mrp2 and increased expression of sinusoidal Mrp3 in NASH and may correlate to increased antinociception by M6G. Increased metabolism and altered transporter regulation in NASH provide a mechanistic basis for interindividual variability in morphine disposition that may lead to opioid-related toxicity.

Footnotes

    • Received October 15, 2014.
    • Accepted December 12, 2014.
  • This research was supported by the National Institutes of Health National Institute of Environmental Health Sciences [Toxicology Training Grant T32-ES007091]; the National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development [Grant R01-HD062489]; and the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant R01-DK068039].

  • dx.doi.org/10.1124/jpet.114.220764.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 352 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 352, Issue 3
1 Mar 2015
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Research ArticleMetabolism, Transport, and Pharmacogenomics

Morphine Disposition in Nonalcoholic Steatohepatitis

Anika L. Dzierlenga, John D. Clarke, Tiffanie L. Hargraves, Garrett R. Ainslie, Todd W. Vanderah, Mary F. Paine and Nathan J. Cherrington
Journal of Pharmacology and Experimental Therapeutics March 1, 2015, 352 (3) 462-470; DOI: https://doi.org/10.1124/jpet.114.220764

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Research ArticleMetabolism, Transport, and Pharmacogenomics

Morphine Disposition in Nonalcoholic Steatohepatitis

Anika L. Dzierlenga, John D. Clarke, Tiffanie L. Hargraves, Garrett R. Ainslie, Todd W. Vanderah, Mary F. Paine and Nathan J. Cherrington
Journal of Pharmacology and Experimental Therapeutics March 1, 2015, 352 (3) 462-470; DOI: https://doi.org/10.1124/jpet.114.220764
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