Simvastatin (SIM)-induced myopathy is a dose-dependent adverse drug reaction (ADR) that has been reported in the clinic. The pharmacokinetics of SIM hydroxy acid (SIMA), the bioactive form of SIM, is linked to the function of the organic anion transporting polypeptide (Oatp) hepatic uptake transporters. Nonalcoholic steatohepatitis (NASH) 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 rodent model of NASH. Diet-induced NASH caused increased plasma retention and decreased biliary excretion of SIMA because of decreased protein expression of multiple hepatic Oatps. SIM exhibited increased volume of distribution in NASH as evident from increased muscle, decreased plasma, and no change in biliary concentrations. These data suggest that NASH-mediated transporter regulation may play a role in altered SIMA disposition and the occurrence of myopathy.
See article at J Pharmacol Exp Ther 2014, 348:452–458.
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