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Vol. 30, Issue 11, 1280-1287, November 2002
Department of Drug Metabolism, Merck Research Laboratories, West
Point, Pennsylvania
This study investigated the metabolic interaction between fibrates
and statin hydroxy acids in human hepatocytes. Gemfibrozil (GFZ)
modestly affected the formation of 
-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 -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
(Ki = 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 -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.
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