PPAR alpha agonists including clofibrate, bezafibrate or fenofibrate showed an increased risk for cholelithiasis (increase of cholesterol gallstones)
however, gemfibrozil appears less lithogenic compared to bezafibrate or clofibrate
possible mechanism underlying fibrate-induced lithogenicity could be the increased biliary output of cholesterol and the reduction of bile acid production via the PPAR alpha-mediated down regulation of cholesterol 7alpha-hydroxylase (Cyp7a) and sterol 27-hydroxylase
however, based on the relative ability of different PPAR alpha ligands to cause cholelithiasis, other mechanisms contributing to this effect cannot be excluded.
Reference:
1. Rubestrunk A et al. Safety issues and prospects for future generations of PPAR modulators Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 2007; 1771 (8): 1065-1081.
2. Mazzella F et al. Effect of gemfibrozil administration on biliary lipid secretion in hyperlipidemic patients. A crossover study with clofibrate, Scand. J. Gastroenterol. 1990;25: 1227-1234.
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