Effects of fibrates on metabolism of statins in human hepatocytes.
This study investigated the metabolic interaction between fibrates and statin hydroxy acids in human hepatocytes. Gemfibrozil (GFZ) modestly affected the formation of beta-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 beta-oxidation product (IC(50) approximately 50 and 15 microM, respectively). In contrast, fenofibrate had a minimal effect on all the metabolic pathways of SVA. GFZ also significantly inhibited (IC(50) approximately 50-60 microM) the oxidation of cerivastatin (CVA) and rosuvastatin (RVA), but not of atorvastatin (AVA), while effectively decreasing (IC(50) approximately 30 to 60 microM) 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 microM) 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 beta-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.
Prueksaritanont
Thomayant
T
Department of Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. thomayant_prueksaritanont@merck.com
Tang
Cuyue
C
Qiu
Yue
Y
Mu
Lillian
L
Subramanian
Raju
R
Lin
Jiunn H
JH
D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D000069059:Atorvastatin; D065727:Cytochrome P-450 CYP2C8; D011345:Fenofibrate / Q000494:pharmacology*; D005464:Fluorobenzenes / Q000378:metabolism; D015248:Gemfibrozil / Q000494:pharmacology*; D014453:Glucuronosyltransferase / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006538:Heptanoic Acids / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism*; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010084:Oxidation-Reduction; D011743:Pyrimidines; D011758:Pyrroles / Q000378:metabolism; D000068718:Rosuvastatin Calcium; D019821:Simvastatin / Q000378:metabolism*; D013449:Sulfonamides
D005464:Fluorobenzenes; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D000069059:Atorvastatin; D019821:Simvastatin; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D014453:Glucuronosyltransferase; D015248:Gemfibrozil; D011345:Fenofibrate