Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum of histopathologies that range from simple steatosis to the more severe steatohepatitis (termed non-alcoholic steatohepatitis or NASH). NAFLD is the most common cause of liver disease in preadolescents and adolescents, and the increased prevalence coincides with the rise in childhood obesity, insulin resistance, and hyperlipidemia. One of the major causes of adverse drug reactions is the inability of the individual patient to handle a standard dose of a prescribed drug. A major goal of individualized medicine is to identify the appropriate dose of a drug that will not elicit an adverse response in that patient. A major factor in determining a safe dose of a drug is the capacity of the patient to metabolize and eliminate that drug from the body. Identifying individuals with an impaired capacity to handle a drug prior to initiating treatment would therefore be instrumental in decreasing the number of adverse drug reactions. For the vast majority of drugs, the liver plays a key role in determining the rate at which drugs are eliminated. Several processes are required for efficient hepatic elimination, including entry into hepatocytes by uptake transporters, Phase I and II biotransformation, and efflux from the liver by drug transporters either into bile or back into the blood. Because the liver plays such a critical role in drug metabolism and disposition, any disease state that disrupts or modifies these functions will alter the fate of numerous drugs within the body. The effect of steatosis and NASH on the expression and activity of the major drug metabolizing enzymes is completely unknown, but could have broad implications in identifying both the patients that are at greater risk of developing adverse drug reactions, and the drugs that are likely to cause adverse events in patients with NASH. Our preliminary results in rodent models and humans with NASH indicate significant changes in the expression of drug metabolizing enzymes and transporters, as well as a functional shift in the disposition of drugs. The two major hypotheses to be addressed are;(1) NASH alters the expression and function of major drug metabolizing enzymes and transporters thereby, increasing the risk of adverse drug reactions in children with NASH and (2) Plasma and/or urine levels of APAP-GLUC can be used as a metabolomic biomarker to identify these patients (with NASH) that may be at risk for adverse drug reactions.
Aim 1. Determine whether the in vivo activity of the major CYP enzymes is altered in children with steatosis or NASH.
Aim 2. Determine whether the functional disposition of APAP metabolites is altered in patients with fatty liver disease.
Aim 3. Determine whether the expression and activity of Phase II and III drug metabolizing enzymes and transporters are altered in human livers diagnosed with steatosis and NASH.

Public Health Relevance

Numerous adverse drug reactions result from the inability of a patient to metabolize and eliminate the standard dose of a drug. Pediatric fatty liver disease may alter the expression of specific drug metabolizing enzymes and transporters which could alter the pharmacokinetics of numerous drugs, thereby increasing the risk of adverse reactions. The current application is designed to determine the effect of NAFLD on the major drug metabolizing enzymes and transporters and whether we can identify patients that are at greater risk of adverse drug reactions before they begin new therapies.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD062489-02
Application #
8209030
Study Section
Special Emphasis Panel (ZRG1-CB-L (50))
Program Officer
Zajicek, Anne
Project Start
2010-12-27
Project End
2015-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
2
Fiscal Year
2012
Total Cost
$321,938
Indirect Cost
$109,438
Name
University of Arizona
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
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Dzierlenga, A L; Clarke, J D; Cherrington, N J (2016) Nonalcoholic Steatohepatitis Modulates Membrane Protein Retrieval and Insertion Processes. Drug Metab Dispos 44:1799-1807
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Clarke, John D; Cherrington, Nathan J (2015) Nonalcoholic steatohepatitis in precision medicine: Unraveling the factors that contribute to individual variability. Pharmacol Ther 151:99-106
Lake, April D; Novak, Petr; Shipkova, Petia et al. (2015) Branched chain amino acid metabolism profiles in progressive human nonalcoholic fatty liver disease. Amino Acids 47:603-15
Merrell, Matthew D; Nyagode, Beatrice A; Clarke, John D et al. (2014) Selective and cytokine-dependent regulation of hepatic transporters and bile acid homeostasis during infectious colitis in mice. Drug Metab Dispos 42:596-602

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