Species differences in the elimination of a peroxisome proliferator-activated receptor agonist highlighted by oxidative metabolism of its acyl glucuronide.
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 alpha-weighted dual peroxisome proliferator-activated receptor alpha/gamma 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.
Kochansky
Christopher J
CJ
Department of Drug Metabolism, Merck Research Laboratories, Rahway, New Jersey, USA. Christopher_Kochansky@merck.com
Xia
Yuan-Qing
YQ
Wang
Sui
S
Cato
Brian
B
Creighton
Mellissa
M
Vincent
Stella H
SH
Franklin
Ronald B
RB
Reed
James R
JR
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004285:Dogs; D020719:Glucuronides / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000378:metabolism*; D008253:Macaca mulatta; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D011422:Propionates / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
C503385:2-((5,7-dipropyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl)oxy)-2-methyl propionic acid; D020719:Glucuronides; D007555:Isoxazoles; D011422:Propionates; D003577:Cytochrome P-450 Enzyme System