Differential Effects of Silymarin on Pitavastatin Disposition in Rodent Models of Simple Fatty Liver versus Nonalcoholic Steatohepatitis: A Natural Product‐Disease‐Drug Interaction

Nonalcoholic fatty liver disease (NAFLD) progresses from simple fatty liver (SFL) to nonalcoholic steatohepatitis (NASH). This progression alters hepatic organic anion transporting polypeptide (OATP/Oatp) uptake transporters and the pharmacokinetics of some xenobiotics after intravenous administration. Comparatively less is known about how diet‐induced NAFLD alters xenobiotic pharmacokinetics after oral administration. Investigation of NAFLD pharmacotherapy options has included the natural product silymarin. How silymarin‐mediated inhibition of transporters interacts with NASH‐associated changes in transporters is not known. The objective of this study was to assess the interaction between silymarin and the OATP/Oatp substrate pitavastatin in the context of SFL and NASH. Male Sprague Dawley rats were fed different diets to model stages of NAFLD: control (healthy), fructose‐palmitic acid‐cholesterol (SFL), or methionine and choline deficient (NASH). Pitavastatin (2.5 mg/kg) was administered via oral gavage, silymarin (500 mg/kg) or vehicle was administered 40 minutes later via oral gavage, and plasma was collected serially from the tail vein to 27 hours. Silymarin flavonolignans and pitavastatin were measured by LC‐MS/MS, and the pharmacokinetics were determined using noncompartmental methods. Trend analysis indicated that C max values for the silymarin flavonolignans and corresponding glucuronides increased from healthy to SFL to NASH. These data are the first to show that SFL alters a pharmacokinetic endpoint and suggest that certain intestinal and/or hepatic mediators change incrementally during NAFLD progression. Indeed, a decreasing trend in hepatic Oatp1b2 protein expression was observed from healthy to SFL to NASH. NASH alone increased pitavastatin AUC 0‐27h 3.0‐fold compared to the healthy vehicle‐treated group. Silymarin increased pitavastatin AUC 0‐27h in both the healthy and NASH groups by a similar extent (~1.7‐fold increase compared to the respective vehicle‐treated groups for each diet). The combination of NASH and silymarin had the greatest effect on pitavastatin AUC 0‐27h (4.9‐fold increase compared to the healthy vehicle‐treated group). SFL had no effect on pitavastatin disposition but, unexpectedly, the silymarin effect on pitavastatin AUC 0‐27h was diminished in the SFL group (1.3‐fold increase compared to a 1.6‐ and 1.8‐fold increase in the healthy and NASH groups, respectively). The multiple peaks in plasma concentrations of all silymarin flavonolignans after 4 hours were largely abolished in the SFL and NASH groups. These data may implicate changes in microbiome‐mediated glucuronidase activity, enterohepatic cycling, and/or intestinal absorption processes. Collectively, patients with NASH may be at increased risk for adverse silymarin‐drug interactions involving pitavastatin and potentially other OATP substrates. Support or Funding Information This work was supported by the National Institutes of Health grants 4R00ES024455 and U54AT008909 and the Washington State University College of Pharmacy and Pharmaceutical Sciences. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .