ArticleThe Journal of pharmacology and experimental therapeutics2015
Mechanistic basis of altered morphine disposition in nonalcoholic steatohepatitis.
Article in The Journal of pharmacology and experimental therapeutics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 50 citations in OpenAlex.
- Influence of Morbid Obesity on the Pharmacokinetics of Morphine, Morphine-3-Glucuronide, and Morphine-6-Glucuronide.Clinical pharmacokinetics · 2017Trial
- Nonalcoholic steatohepatitis increases plasma retention of sorafenib-glucuronide in a mouse model by altering hepatocyte hopping.Acta pharmaceutica Sinica. B · 2024Article
- Improvement of Type 2 Diabetes Mellitus and Attenuation of NAFLD Are Associated with the Success of Obesity Therapy.Journal of clinical medicine · 2022Article
- Role of Insulin Resistance in MAFLD.International journal of molecular sciences · 2021Review
- Physiologically-Based Pharmacokinetic Model of Morphine and Morphine-3-Glucuronide in Nonalcoholic Steatohepatitis.Clinical pharmacology and therapeutics · 2021Article
- Interaction of Oatp1b2 expression and nonalcoholic steatohepatitis on pravastatin plasma clearance.Biochemical pharmacology · 2020Article
- A Pharmacokinetic Natural Product-Disease-Drug Interaction: A Double Hit of Silymarin and Nonalcoholic Steatohepatitis on Hepatic Transporters in a Rat Model.The Journal of pharmacology and experimental therapeutics · 2019Article
- Gene-by-Environment Interaction of BcrpDrug metabolism and disposition: the biological fate of chemicals · 2018Article
- Alcohol Metabolism in the Progression of Human Nonalcoholic Steatohepatitis.Toxicological sciences : an official journal of the Society of Toxicology · 2018Article
- Misregulation of membrane trafficking processes in human nonalcoholic steatohepatitis.Journal of biochemical and molecular toxicology · 2018Article
- Asking the Right Questions With Animal Models: Methionine- and Choline-Deficient Model in Predicting Adverse Drug Reactions in Human NASH.Toxicological sciences : an official journal of the Society of Toxicology · 2018Article
- Pediatric Cytochrome P450 Activity Alterations in Nonalcoholic Steatohepatitis.Drug metabolism and disposition: the biological fate of chemicals · 2017Article
- Renal Drug Transporters and Drug Interactions.Clinical pharmacokinetics · 2017Review
- Impaired N-linked glycosylation of uptake and efflux transporters in human non-alcoholic fatty liver disease.Liver international : official journal of the International Association for the Study of the Liver · 2017Article
- Population Pharmacokinetics of Morphine in Patients With Nonalcoholic Steatohepatitis (NASH) and Healthy Adults.CPT: pharmacometrics & systems pharmacology · 2017Article
- Non-alcoholic fatty liver disease (NAFLD) - pathogenesis, classification, and effect on drug metabolizing enzymes and transporters.Drug metabolism reviews · 2017Review
- Impact of Nonalcoholic Fatty Liver Disease on Toxicokinetics of Tetrachloroethylene in Mice.The Journal of pharmacology and experimental therapeutics · 2017Article
- In vivo cytochrome P450 activity alterations in diabetic nonalcoholic steatohepatitis mice.Journal of biochemical and molecular toxicology · 2017Article
- Nonalcoholic Steatohepatitis Modulates Membrane Protein Retrieval and Insertion Processes.Drug metabolism and disposition: the biological fate of chemicals · 2016Article
- Effect of nonalcoholic steatohepatitis on renal filtration and secretion of adefovir.Biochemical pharmacology · 2016Article
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
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.
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