PT - JOURNAL ARTICLE AU - Vijay Bhasker G. Reddy AU - George A. Doss AU - Mellissa Creighton AU - Christopher J. Kochansky AU - Stella H. Vincent AU - Ronald B. Franklin AU - Bindhu V. Karanam TI - IDENTIFICATION AND METABOLISM OF A NOVEL DIHYDROHYDROXY-<em>S</em>-GLUTATHIONYL CONJUGATE OF A PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR AGONIST, MK-0767 [(±)-5-[(2,4-DIOXOTHIAZOLIDIN-5-YL)METHYL]-2-METHOXY-<em>N</em>-[[(4-TRIFLUOROMETHYL) PHENYL]METHYL]BENZAMIDE], IN RATS AID - 10.1124/dmd.104.000240 DP - 2004 Oct 01 TA - Drug Metabolism and Disposition PG - 1154--1161 VI - 32 IP - 10 4099 - http://dmd.aspetjournals.org/content/32/10/1154.short 4100 - http://dmd.aspetjournals.org/content/32/10/1154.full SO - Drug Metab Dispos2004 Oct 01; 32 AB - 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 α/γ 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. The American Society for Pharmacology and Experimental Therapeutics