Received for publication February 20, 2007.
Revised April 19, 2007.
Accepted for publication April 25, 2007.

Atorvastatin Glucuronidation is Minimally and Non-Selectively Inhibited by the Fibrates Gemfibrozil, Fenofibrate and Fenofibric Acid

Abstract

Gemfibrozil co-administration generally results in plasma statin 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 (Prueksaritanont et al. (2002) Drug Metab Dispos 30:1280-7). This study was conducted to determine the in vitro inhibitory potential of fibrates towards atorvastatin glucuronidation. [³H]atorvastatin, atorvastatin, and atorvastatin lactone were incubated with human liver microsomes (HLM) or human recombinant UDP-glucuronosyltransferases (UGTs) and characterized using LC/MS/MS and LC/UV/-RAM/MS. [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 while G1 formation was catalyzed by UGTs 1A3, 1A4, and 1A9. Gemfibrozil, fenofibrate, and fenofibric acid inhibited atorvastatin lactonization with IC₅₀-values of 346 µM, 320 µM, 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) following gemfibrozil co-administration 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.

Key words: drug-drug interactions, enzyme kinetics, glucuronidation, in vitro-in vivo prediction, structure elucidation, UDP glucuronyltransferases

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