Differential effects of fibrates on the metabolic activation of 2-phenylpropionic acid in rats.
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.
Li
Chunze
C
Department of Biopharmaceutical Sciences, 533 Parnassus Ave., U-68, University of California, San Francisco, CA 94143-0446, USA.
Grillo
Mark P
MP
Badagnani
Ilaria
I
Fife
Kimberly L
KL
Benet
Leslie Z
LZ
D000818:Animals; D001711:Biotransformation / Q000187:drug effects / Q000502:physiology; D002995:Clofibric Acid / Q000493:pharmacokinetics*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010666:Phenylpropionates / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
D010666:Phenylpropionates; D002995:Clofibric Acid; C013025:hydratropic acid