Received for publication February 8, 2005.
Revised September 9, 2005.
Accepted for publication September 20, 2005.

SPECIES DIFFERENCES IN THE ELIMINATION OF A PPAR AGONIST HIGHLIGHTED BY OXIDATIVE METABOLISM OF ITS ACYL GLUCURONIDE

Abstract

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 -weighted dual PPAR/ agonist. Following 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 UDPGA-fortified liver microsomes. However, metabolism was more extensive in the monkey microsomes than 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.

Key words: glucuronidation, metabolite identification, microsomes, peroxisome proliferator-activated receptors, phase II drug metabolism, UDP glucuronyltransferases