RT Journal Article
SR Electronic
T1 SPECIES DIFFERENCES IN THE ELIMINATION OF A PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR AGONIST HIGHLIGHTED BY OXIDATIVE METABOLISM OF ITS ACYL GLUCURONIDE
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1894
OP 1904
DO 10.1124/dmd.105.004010
VO 33
IS 12
A1 Christopher J. Kochansky
A1 Yuan-Qing Xia
A1 Sui Wang
A1 Brian Cato
A1 Mellissa Creighton
A1 Stella H. Vincent
A1 Ronald B. Franklin
A1 James R. Reed
YR 2005
UL http://dmd.aspetjournals.org/content/33/12/1894.abstract
AB A species difference was observed in the excretion pathway of 2-[[5,7-dipropyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy]-2-methylpropanoic acid (MRL-C), an α-weighted dual peroxisome proliferator-activated receptor α/γ agonist. After intravenous or oral administration of [14C]MRL-C to rats and dogs, radioactivity was excreted mainly into the bile as the acyl glucuronide metabolite of the parent compound. In contrast, when [14C]MRL-C was administered to monkeys, radioactivity was excreted into both the bile and the urine as the acyl glucuronide metabolite, together with several oxidative metabolites and their ether or acyl glucuronides. Incubations in hepatocytes from rats, dogs, monkeys, and humans showed the formation of the acyl glucuronide of the parent compound as the major metabolite in all species. The acyl glucuronide and several hydroxylated products, some which were glucuronidated at the carboxylic acid moiety, were observed in incubations of MRL-C with NADPH- and uridine 5′-diphosphoglucuronic acid-fortified liver microsomes. However, metabolism was more extensive in the monkey microsomes than in those from the other species. When the acyl glucuronide metabolite of MRL-C was incubated with NADPH-fortified liver microsomes, in the presence of saccharo-1,4-lactone, it underwent extensive oxidative metabolism in the monkey but considerably less in the rat, dog, and human liver microsomes. Collectively, these data suggested that the oxidative metabolism of the acyl glucuronide might have contributed to the observed in vivo species differences in the metabolism and excretion of MRL-C. The American Society for Pharmacology and Experimental Therapeutics