Abstract

This study investigated the metabolic interaction between fibrates and statin hydroxy acids in human hepatocytes. Gemfibrozil (GFZ) modestly affected the formation of β-oxidative products and CYP3A4-mediated oxidative metabolites of simvastatin hydroxy acid (SVA) but markedly inhibited the glucuronidation-mediated lactonization of SVA and the glucuronidation of a β-oxidation product (IC₅₀ ∼50 and 15 μM, respectively). In contrast, fenofibrate had a minimal effect on all the metabolic pathways of SVA. GFZ also significantly inhibited (IC₅₀ ∼50–60 μM) the oxidation of cerivastatin (CVA) and rosuvastatin (RVA), but not of atorvastatin (AVA), while effectively decreasing (IC₅₀ ∼30 to 60 μM) the lactonization of all three statins. As was observed previously with other statin hydroxy acids, RVA underwent significant glucuronidation to form an acyl glucuronide conjugate and lactonization to form RVA lactone in human liver microsomes and by UGT 1A1 and 1A3. While GFZ is not an inhibitor of CYP3A4, it is a competitive inhibitor (K_i = 87 μM) of CYP2C8, a major catalyzing enzyme for CVA oxidation. These results suggest that 1) the pharmacokinetic interaction observed between GFZ and statins was not likely mediated by the inhibitory effect of GFZ on the β-oxidation, but rather by its effect primarily on the glucuronidation and non-CYP3A-mediated oxidation of statin hydroxy acids, and 2) there is a potential difference between fibrates in their ability to affect the pharmacokinetics of statins, and among statins in their susceptibility to metabolic interactions with GFZ in humans.