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 #
5R01HD062489-04
Application #
8598918
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
2013-12-01
Budget End
2014-11-30
Support Year
4
Fiscal Year
2014
Total Cost
$289,744
Indirect Cost
$98,494
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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Kyriakides, Michael; Hardwick, Rhiannon N; Jin, Zhaosheng et al. (2014) Systems level metabolic phenotype of methotrexate administration in the context of non-alcoholic steatohepatitis in the rat. Toxicol Sci 142:105-16
Klein, David M; Wright, Stephen H; Cherrington, Nathan J (2014) Localization of multidrug resistance-associated proteins along the blood-testis barrier in rat, macaque, and human testis. Drug Metab Dispos 42:89-93
Canet, Mark J; Hardwick, Rhiannon N; Lake, April D et al. (2014) Modeling human nonalcoholic steatohepatitis-associated changes in drug transporter expression using experimental rodent models. Drug Metab Dispos 42:586-95
Canet, Mark J; Cherrington, Nathan J (2014) Drug disposition alterations in liver disease: extrahepatic effects in cholestasis and nonalcoholic steatohepatitis. Expert Opin Drug Metab Toxicol 10:1209-19
Clarke, John D; Novak, Petr; Lake, April D et al. (2014) Characterization of hepatocellular carcinoma related genes and metabolites in human nonalcoholic fatty liver disease. Dig Dis Sci 59:365-74
Clarke, John D; Hardwick, Rhiannon N; Lake, April D et al. (2014) Experimental nonalcoholic steatohepatitis increases exposure to simvastatin hydroxy acid by decreasing hepatic organic anion transporting polypeptide expression. J Pharmacol Exp Ther 348:452-8
Clarke, John D; Hardwick, Rhiannon N; Lake, April D et al. (2014) Synergistic interaction between genetics and disease on pravastatin disposition. J Hepatol 61:139-47
Hardwick, Rhiannon N; Clarke, John D; Lake, April D et al. (2014) Increased susceptibility to methotrexate-induced toxicity in nonalcoholic steatohepatitis. Toxicol Sci 142:45-55
Clarke, John D; Sharapova, Tatiana; Lake, April D et al. (2014) Circulating microRNA 122 in the methionine and choline-deficient mouse model of non-alcoholic steatohepatitis. J Appl Toxicol 34:726-32

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