Identification and metabolism of a novel dihydrohydroxy-S-glutathionyl conjugate of a peroxisome proliferator-activated receptor agonist, MK-0767 [(+/-)-5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[(4-trifluoromethyl) phenyl]methyl]benzamide], in rats.
MK-0767 [(+/-)-5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[(4-trifluoromethyl)phenyl]methyl]benzamide] is a novel thiazolidinedione-containing peroxisome proliferator-activated receptor alpha/gamma agonist. In rats dosed orally with [14C]MK-0767, a dihydrohydroxy-S-glutathionyl conjugate of the parent compound was identified in the bile using liquid chromatography-mass spectometry and 1H NMR techniques. The formation of the conjugate likely proceeded via an arene oxide intermediate. The corresponding cysteinylglycine and cysteinyl conjugates likely formed from the further metabolism of the dihydrohydroxy-S-glutathionyl conjugate also were detected in rat bile. The dihydrohydroxy-S-glutathionyl conjugate was formed in vitro following the incubation of MK-0767 and glutathione with rat, dog, or monkey liver microsomes, and its formation was NADPH-dependent; however, this conjugate was not detected in human liver microsomal incubations. When incubated with rat intestinal contents, the dihydrohydroxy-S-glutathionyl conjugate was reduced to the parent compound (MK-0767), suggesting the involvement of intestinal microflora in its metabolism. There was no reduction of the conjugate by rat intestinal cytosol.
Reddy
Vijay Bhasker G
VB
Department of Drug Metabolism, Merck Research Laboratories, 126 East Lincoln Avenue, Rahway, NJ 07065, USA. g_vijay_reddy@merck.com
Doss
George A
GA
Creighton
Mellissa
M
Kochansky
Christopher J
CJ
Vincent
Stella H
SH
Franklin
Ronald B
RB
Karanam
Bindhu V
BV
D000818:Animals; D004285:Dogs; D005978:Glutathione / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D007421:Intestine, Small / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists* / Q000032:analysis / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*
C487303:MK0767; D047492:Peroxisome Proliferator-Activated Receptors; D013844:Thiazoles; D005978:Glutathione