Modeling human nonalcoholic steatohepatitis-associated changes in drug transporter expression using experimental rodent models

Mark J Canet; Rhiannon N Hardwick; April D Lake; Anika L Dzierlenga; John D Clarke; Nathan J Cherrington

doi:10.1124/dmd.113.055996

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Modeling human nonalcoholic steatohepatitis-associated changes in drug transporter expression using experimental rodent models

Journal article

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Modeling human nonalcoholic steatohepatitis-associated changes in drug transporter expression using experimental rodent models

Mark J Canet, Rhiannon N Hardwick, April D Lake, Anika L Dzierlenga, John D Clarke and Nathan J Cherrington

Drug metabolism and disposition, Vol.42(4), pp.586-595

04/2014

DOI: https://doi.org/10.1124/dmd.113.055996

Handle:

https://hdl.handle.net/2376/108690

PMCID: PMC3965900

PMID: 24384915

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Abstract

Fatty Liver - metabolism

Obesity - complications

Mice, Inbred C57BL

Diabetes Mellitus, Experimental - genetics

Diet, Atherogenic - adverse effects

Rats

Choline Deficiency - complications

Male

Obesity - genetics

Rats, Sprague-Dawley

Organic Anion Transporters - metabolism

Tissue Distribution

Organic Anion Transporters - genetics

Pharmaceutical Preparations - metabolism

Animals

Diabetes Mellitus, Experimental - complications

Mice

Disease Models, Animal

Fatty Liver - etiology

Methionine - deficiency

Nonalcoholic fatty liver disease is a prevalent form of chronic liver disease that can progress to the more advanced stage of nonalcoholic steatohepatitis (NASH). NASH has been shown to alter drug transporter regulation and may have implications in the development of adverse drug reactions. Several experimental rodent models have been proposed for the study of NASH, but no single model fully recapitulates all aspects of the human disease. The purpose of the current study was to determine which experimental NASH model best reflects the known alterations in human drug transporter expression to enable more accurate drug disposition predictions in NASH. Both rat and mouse NASH models were used in this investigation and include the methionine and choline deficient (MCD) diet model, atherogenic diet model, ob/ob and db/db mice, and fa/fa rats. Pathologic scoring evaluations demonstrated that MCD and atherogenic rats, as well as ob/ob and db/db mice, developed NASH. Liver mRNA and protein expression analyses of drug transporters showed that in general, efflux transporters were induced and uptake transporters were repressed in the rat MCD and the mouse ob/ob and db/db models. Lastly, concordance analyses suggest that both the mouse and rat MCD models as well as mouse ob/ob and db/db NASH models show the most similarity to human transporter mRNA and protein expression. These results suggest that the MCD rat and mouse model, as well as the ob/ob and db/db mouse models, may be useful for predicting altered disposition of drugs with similar kinetics across humans and rodents.

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Title: Modeling human nonalcoholic steatohepatitis-associated changes in drug transporter expression using experimental rodent models
Creators: Mark J Canet - University of Arizona, Department of Pharmacology and Toxicology, Tucson, Arizona
Rhiannon N Hardwick
April D Lake
Anika L Dzierlenga
John D Clarke
Nathan J Cherrington
Publication Details: Drug metabolism and disposition, Vol.42(4), pp.586-595
Academic Unit: Pharmaceutical Sciences, Department of
Publisher: United States
Grant note: HD062489 / NICHD NIH HHS R01 AI083927 / NIAID NIH HHS T32 ES007091 / NIEHS NIH HHS ES007091 / NIEHS NIH HHS R01 HD062489 / NICHD NIH HHS AI083927 / NIAID NIH HHS P30 ES006694 / NIEHS NIH HHS ES006694 / NIEHS NIH HHS
Identifiers: 99900547115501842
Language: English
Resource Type: Journal article