RT Journal Article SR Electronic T1 IN VITRO METABOLISM OF MK-0767 [(±)-5-[(2,4-DIOXOTHIAZOLIDIN-5-YL)METHYL]-2-METHOXY-N-[[(4-TRIFLUOROMETHYL) PHENYL]METHYL]BENZAMIDE], A PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR α/γ AGONIST. I. ROLE OF CYTOCHROME P450, METHYLTRANSFERASES, FLAVIN MONOOXYGENASES, AND ESTERASES JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 1015 OP 1022 DO 10.1124/dmd.104.000034 VO 32 IS 9 A1 Bindhu V. Karanam A1 Cornelis E.C.A. Hop A1 David Q. Liu A1 Mike Wallace A1 Dennis Dean A1 Hiroya Satoh A1 Masakatsu Komuro A1 Katsuya Awano A1 Stella H. Vincent YR 2004 UL http://dmd.aspetjournals.org/content/32/9/1015.abstract AB The metabolism of MK-0767, (±)-5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[(4-trifluoromethyl) phenyl]methyl]benzamide, a thiazolidinedione (TZD)-containing peroxisome proliferator-activated receptor α/γ agonist, was studied in liver microsomes and hepatocytes from humans and rat, dog, and rhesus monkey, to characterize the enzyme(s) involved in its metabolism. The major site of metabolism is the TZD ring, which underwent opening catalyzed by CYP3A4 to give the mercapto derivative, M22. Other metabolites formed in NADPH-fortified liver microsomes included the TZD-5-OH derivative (M24), also catalyzed by CYP3A4, and the O-desmethyl derivative (M28), whose formation was catalyzed by CYP2C9 and CYP2C19. Metabolite profiles from hepatocyte incubations were different from those generated with NADPH-fortified microsomal incubations. In addition to M22, M24, and M28, hepatocytes generated several S-methylated metabolites, including the methyl mercapto (M25), the methyl sulfoxide amide (M16), and the methyl sulfone amide (M20) metabolites. Addition of the methyl donor, S-adenosyl methionine, in addition to NADPH, to microsomal incubations enhanced the turnover and resulted in metabolite profiles similar to those in hepatocyte incubations. Collectively, these results indicated that methyltransferases played a major role in the metabolism of MK-0767. Using enzyme-specific inhibitors, it was concluded that microsomal thiol methyltransferases play a more important role than the cytosolic thiopurine methyltransferase. Baculovirus-expressed human flavin-containing monooxygenase 3, as well as CYP3A4, oxidized M25 to M16, whereas further oxidation of M16 to M20 was catalyzed mainly by CYP3A4. Esterases were involved in the formation of the methyl sulfone carboxylic acids, minor metabolites detected in hepatocytes. The American Society for Pharmacology and Experimental Therapeutics