Experimental nonalcoholic steatohepatitis increases exposure to simvastatin hydroxy acid by decreasing hepatic organic anion transporting polypeptide expression

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

doi:10.1124/jpet.113.211284

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Experimental nonalcoholic steatohepatitis increases exposure to simvastatin hydroxy acid by decreasing hepatic organic anion transporting polypeptide expression

Journal article

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Experimental nonalcoholic steatohepatitis increases exposure to simvastatin hydroxy acid by decreasing hepatic organic anion transporting polypeptide expression

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

The Journal of pharmacology and experimental therapeutics, Vol.348(3), pp.452-458

03/2014

DOI: https://doi.org/10.1124/jpet.113.211284

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https://hdl.handle.net/2376/108386

PMCID: PMC3935144

PMID: 24403518

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Abstract

Fatty Liver - metabolism

Simvastatin - adverse effects

Down-Regulation

Liver - metabolism

Simvastatin - metabolism

Rats

Male

Rats, Sprague-Dawley

Organic Anion Transporters - metabolism

Simvastatin - analogs & derivatives

Animals

Hydroxymethylglutaryl-CoA Reductase Inhibitors - adverse effects

Hydroxymethylglutaryl-CoA Reductase Inhibitors - metabolism

Non-alcoholic Fatty Liver Disease

Simvastatin (SIM)-induced myopathy is a dose-dependent adverse drug reaction (ADR) that has been reported to occur in 18.2% of patients receiving a 40- to 80-mg dose. The pharmacokinetics of SIM hydroxy acid (SIMA), the bioactive form of SIM, and the occurrence of SIM-induced myopathy are linked to the function of the organic anion transporting polypeptide (Oatp) hepatic uptake transporters. Genetic polymorphisms in SLCO1B1, the gene for human hepatic OATP1B1, cause decreased elimination of SIMA and increased risk of developing myopathy. Nonalcoholic steatohepatitis (NASH) is the most severe form of nonalcoholic fatty liver disease, and is known to alter drug transporter expression and drug disposition. The purpose of this study was to assess the metabolism and disposition of SIM in a diet-induced rodent model of NASH. Rats were fed a methionine- and choline-deficient diet for 8 weeks to induce NASH and SIM was administered intravenously. Diet-induced NASH caused increased plasma retention and decreased biliary excretion of SIMA due to decreased protein expression of multiple hepatic Oatps. SIM exhibited increased volume of distribution in NASH as evidenced by increased muscle, decreased plasma, and no change in biliary concentrations. Although Cyp3a and Cyp2c11 proteins were decreased in NASH, no alterations in SIM metabolism were observed. These data, in conjunction with our previous data showing that human NASH causes a coordinated downregulation of hepatic uptake transporters, suggest that NASH-mediated transporter regulation may play a role in altered SIMA disposition and the occurrence of myopathy.

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Title: Experimental nonalcoholic steatohepatitis increases exposure to simvastatin hydroxy acid by decreasing hepatic organic anion transporting polypeptide expression
Creators: John D Clarke - Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona
Rhiannon N Hardwick
April D Lake
Mark J Canet
Nathan J Cherrington
Publication Details: The Journal of pharmacology and experimental therapeutics, Vol.348(3), pp.452-458
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 R01 HD062489 / NICHD NIH HHS AI083927 / NIAID NIH HHS P30 ES006694 / NIEHS NIH HHS T32-ES007091 / NIEHS NIH HHS
Identifiers: 99900547369001842
Language: English
Resource Type: Journal article