RT Journal Article
SR Electronic
T1 Differential Effects of Fibrates on the Metabolic Activation of 2-Phenylpropionic Acid in Rats
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 682
OP 687
DO 10.1124/dmd.107.017764
VO 36
IS 4
A1 Chunze Li
A1 Mark P. Grillo
A1 Ilaria Badagnani
A1 Kimberly L. Fife
A1 Leslie Z. Benet
YR 2008
UL http://dmd.aspetjournals.org/content/36/4/682.abstract
AB A series of studies were conducted to explore the inductive potential of different fibric acid derivatives on the two alternative metabolic activation pathways of 2-phenylpropionic acid (2-PPA) (a model substrate for profen drugs), namely acyl-CoA formation and acyl glucuronidation, in vivo in rats, and to evaluate whether such treatment could potentially modulate the covalent binding of profens to hepatic protein. After administration of a single dose of 2-PPA (130 mg/kg) to rats pretreated with equimolar doses of clofibric acid (160 mg/kg/day), fenofibrate (260 mg/kg/day), or gemfibrozil (180 mg/kg/day) for 7 days, rat livers were collected and analyzed for covalent binding and hepatic levels of the two reactive metabolites over a 2-h period. Results showed that the three fibrates exhibited very different effects on the hepatic levels of 2-PPA-S-acyl CoA (2-PPA-CoA) in vivo, even though all three significantly increased acyl-CoA synthetase activity in vitro in liver homogenate. Treatment with clofibric acid markedly increased the hepatic exposure of 2-PPA-CoA by 2.9-fold and led to a 25% increase (p < 0.05) in covalent binding of 2-PPA to liver protein. In contrast, significant decreases of the hepatic levels of 2-PPA acyl glucuronide and/or 2-PPA-CoA by fenofibrate and gemfibrozil significantly lowered the covalent binding of 2-PPA to hepatic protein. Together, these results suggest that fibrates exhibit markedly different abilities to alter the extent of covalent binding of 2-PPA to hepatic protein by differentially modulating the hepatic exposure of the two reactive metabolites of 2-PPA, namely 2-PPA-CoA thioester and acyl glucuronide.