Chemogenomics analysis reveals potential molecular mechanism of the drug‐drug interaction between statins and fibrates

The incidence of HMG‐CoA reductase inhibitor (statin) associated rhabdomyolysis increases with co‐administration of a PPARα agonist (fibrate) due to drug‐drug interaction (DDI) between these two classes of lipid lowering agents. This DDI was initially considered to be a pharmacodynamic effect since both classes of drugs can cause myopathy when administered alone; however, recently gemfibrozil was reported to increase the plasma concentration of cerivastatin by 5‐fold. We have analyzed drug‐induced gene expression changes in liver and skeletal muscle tissues of statin or fibrate‐treated (MTD) rats and found that the pharmacodynamic effect may be attributed to insufficient hepatic glucose output resulting from synergistic down‐regulation of key genes involved in hepatic gluconeogenesis, PEPCK and glucose‐6‐phosphatase, by fibrates and statins, respectively. The state of glucose‐insufficiency in skeletal muscles of statin‐treated animals was reflected in i) the up‐regulation of PDK4 ‐ known to be induced both under conditions of starvation and by PPARα agonists, and ii) increased expression of mitochondrial HMG‐CoA synthase, the rate limiting enzyme for ketogenesis. We have also found that fibrates suppress CYP2C, CYP3A, PAPSS2 and ABCC2 which are involved in the metabolism and excretion of the statins, potentially leading to increased plasma concentration of co‐administered statins.