Modeling Human Nonalcoholic Steatohepatitis-Associated Changes in Drug Transporter Expression Using Experimental Rodent Models

Abstract

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.

Mechanistic Basis of Altered Morphine Disposition in Nonalcoholic Steatohepatitis

“…1). Rats that received the 8-week MCD diet exhibited NASH hallmarks, including steatosis, inflammation, and fibrosis, consistent with previous reports wherein this model was scored by a trained pathologist using a validated NASH scoring system (Kleiner et al, 2005;Canet et al, 2014) and identified as histologically similar to human NASH (George et al, 2003). The effect of NASH on morphine and M3G disposition after intravenous administration of morphine was examined over 150 minutes.…”

Renal Xenobiotic Transporter Expression is Altered in Multiple Experimental Models of Nonalcoholic Steatohepatitis

“…It is proposed that Mrp2 induction in the kidneys may serve as an alternative route of elimination of bile acids in situations in which liver function is compromised (Klaassen and Aleksunes, 2010). Similar to cholestasis, hepatic Mrp2 function is significantly reduced in NASH whereas Mrp4 is induced, leading to a functional shift in the disposition of xenobiotics from bile to plasma Canet et al, 2014). The similarity in the changes to hepatic and renal transporter gene expression between cholestasis and NASH is suggestive of a common mechanism mediating these effects.…”

“…Indeed, NASH causes extensive alterations in the regulation of hepatic xenobiotic transporters of both human and rodent models, leading to the functional disruption of acetaminophen, ezetimibe, methotrexate, and arsenic disposition (Lickteig et al, 2007;Hardwick et al, 2011Hardwick et al, , 2012Canet et al, 2012Canet et al, , 2014. A common observation in these studies is increased plasma retention coupled with decreased biliary elimination of xenobiotics, suggesting that patients with NASH may represent a unique population of individuals that are at higher risk of experiencing adverse drug reactions.…”

“…This allows for a more thorough and accurate analysis of the disease on renal transporter regulation. NASH pathology and liver membrane transporter expression was characterized previously (Canet et al, 2014;Supplemental Fig. 1).…”

“…Kidney sections were evaluated and scored for renal injury. Liver sections were injury scored according to a previously validated NASH scoring method (Kleiner et al, 2005), and the results were published previously (Canet et al, 2014).…”