PT  - JOURNAL ARTICLE
AU  - Theunis C. Goosen
AU  - Jonathan N. Bauman
AU  - John A. Davis
AU  - Chongwoo Yu
AU  - Susan I. Hurst
AU  - J. Andrew Williams
AU  - Cho-Ming Loi
TI  - Atorvastatin Glucuronidation Is Minimally and Nonselectively Inhibited by the Fibrates Gemfibrozil, Fenofibrate, and Fenofibric Acid
AID  - 10.1124/dmd.107.015230
DP  - 2007 Aug 01
TA  - Drug Metabolism and Disposition
PG  - 1315--1324
VI  - 35
IP  - 8
4099  - http://dmd.aspetjournals.org/content/35/8/1315.short
4100  - http://dmd.aspetjournals.org/content/35/8/1315.full
SO  - Drug Metab Dispos2007 Aug 01; 35
AB  - Gemfibrozil coadministration generally results in plasma statin area under the curve (AUC) increases, ranging from moderate (2- to 3-fold) with simvastatin, lovastatin, and pravastatin to most significant with cerivastatin (5.6-fold). Inhibition of statin glucuronidation has been postulated as a potential mechanism of interaction (Drug Metab Dispos 30:1280–1287, 2002). This study was conducted to determine the in vitro inhibitory potential of fibrates toward atorvastatin glucuronidation. [3H]Atorvastatin, atorvastatin, and atorvastatin lactone were incubated with human liver microsomes or human recombinant UDP-glucuronosyltransferases (UGTs) and characterized using liquid chromatography (LC)/tandem mass spectrometry and LC/UV/β-radioactivity monitor/mass spectrometry. [3H]Atorvastatin yields a minor ether glucuronide (G1) and a major acyl glucuronide (G2) with subsequent pH-dependent lactonization of G2 to yield atorvastatin lactone. Atorvastatin lactonization best fit substrate inhibition kinetics (Km = 12 μM, Vmax = 74 pmol/min/mg, Ki = 75 μM). Atorvastatin lactone yields a single ether glucuronide (G3). G3 formation best fit Michaelis-Menten kinetics (Km = 2.6 μM, Vmax = 10.6 pmol/min/mg). Six UGT enzymes contribute to atorvastatin glucuronidation with G2 and G3 formation catalyzed by UGTs 1A1, 1A3, 1A4, 1A8, and 2B7, whereas G1 formation was catalyzed by UGTs 1A3, 1A4, and 1A9. Gemfibrozil, fenofibrate, and fenofibric acid inhibited atorvastatin lactonization with IC50 values of 346, 320, and 291 μM, respectively. Based on unbound fibrate concentrations at the inlet to the liver, these data predict a small increase in atorvastatin AUC (∼1.2-fold) after gemfibrozil coadministration and no interaction with fenofibrate. This result is consistent with recent clinical reports indicating minimal atorvastatin AUC increases (∼1.2- to 1.4-fold) with gemfibrozil. The American Society for Pharmacology and Experimental Therapeutics