title: Experimental nonalcoholic steatohepatitis increases exposure to simvastatin hydroxy acid by decreasing hepatic organic anion transporting polypeptide expression.
abstract: 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.
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona.
authors.forename: John D
authors.initials: JD
authors.lastname: Clarke
authors.forename: Rhiannon N
authors.initials: RN
authors.lastname: Hardwick
authors.forename: April D
authors.initials: AD
authors.lastname: Lake
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Canet
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Cherrington
mesh_terms: D000818:Animals; D015536:Down-Regulation; D005234:Fatty Liver / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease; D027361:Organic Anion Transporters / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027361:Organic Anion Transporters; C532833:simvastatin hydroxyacid; D019821:Simvastatin