QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: dmd.107.015230v1 35/8/1315    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Goosen, T. C. Articles by Loi, C.-M. Search for Related Content PubMed PubMed Citation Articles by Goosen, T. C. Articles by Loi, C.-M.

Atorvastatin Glucuronidation Is Minimally and Nonselectively Inhibited by the Fibrates Gemfibrozil, Fenofibrate, and Fenofibric Acid

Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Ann Arbor, Michigan

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/ß-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 (K_m = 12 µM, V_max = 74 pmol/min/mg, K_i = 75 µM). Atorvastatin lactone yields a single ether glucuronide (G3). G3 formation best fit Michaelis-Menten kinetics (K_m = 2.6 µM, V_max = 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.

This article has been cited by other articles:

				Y. Mano, T. Usui, and H. Kamimura The UDP-Glucuronosyltransferase 2B7 Isozyme Is Responsible for Gemfibrozil Glucuronidation in the Human Liver Drug Metab. Dispos., November 1, 2007; 35(11): 2040 - 2044. [Abstract] [Full Text] [PDF]