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, Nathan J Cherrington

Research output: Contribution to journalArticle

25 Citations (Scopus)

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 canalicularmembrane, 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 formorphine 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 theM3G/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 sinusoidalMrp3 in NASH andmay 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.

Original languageEnglish (US)
Pages (from-to)462-470
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume352
Issue number3
DOIs
StatePublished - Mar 1 2015

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Morphine
Bile
Diet
Multidrug Resistance-Associated Proteins
Glucuronosyltransferase
Non-alcoholic Fatty Liver Disease
Liver
Xenobiotics
Choline
Methionine
Opioid Analgesics
Sprague Dawley Rats
Up-Regulation
Urine
Kidney
morphine-6-glucuronide
morphine-3-glucuronide
Enzymes

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

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Mechanistic basis of altered morphine disposition in nonalcoholic steatohepatitis. / Dzierlenga, Anika L.; Clarke, John D.; Hargraves, Tiffanie L.; Ainslie, Garrett R.; Vanderah, Todd W; Paine, Mary F.; Cherrington, Nathan J.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 352, No. 3, 01.03.2015, p. 462-470.

Research output: Contribution to journalArticle

Dzierlenga, Anika L. ; Clarke, John D. ; Hargraves, Tiffanie L. ; Ainslie, Garrett R. ; Vanderah, Todd W ; Paine, Mary F. ; Cherrington, Nathan J. / Mechanistic basis of altered morphine disposition in nonalcoholic steatohepatitis. In: Journal of Pharmacology and Experimental Therapeutics. 2015 ; Vol. 352, No. 3. pp. 462-470.
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