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Absorption, Metabolism, and Excretion of [¹⁴C]MK-0767 (2-Methoxy-5-(2,4-dioxo-5-thiazolidinyl)-N-[[4-(trifluoromethyl)phenyl] methyl]benzamide) in Humans

Department of Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania (C.J.K., R.K.R., K.X.Y., H.S.) and Rahway, New Jersey (M.A.W., D.D., A.N.J., S.H.V., R.B.F.); Department of Clinical Pharmacology, Merck Research Laboratories, Rahway, New Jersey (J.S., J.W.); and Clinical Pharmacology Associates, Miami, Florida (K.L.)

MK-0767 (KRP-297; 2-methoxy-5-(2,4-dioxo-5-thiazolidinyl)-N-[[4-(trifluoromethyl)phenyl] methyl]benzamide) is a thiazolidinedione (TZD)-containing dual agonist of the peroxisome proliferator-activated receptors and that has been studied as a potential treatment for patients with type 2 diabetes. The metabolism and excretion of [¹⁴C]MK-0767 were evaluated in six human volunteers after a 5-mg (200 µCi) oral dose. Excretion of ¹⁴C radioactivity was found to be nearly equal into the urine (50%) and feces (40%). Elimination of [¹⁴C]MK-0767 was primarily by metabolism, with minimal excretion of parent compound into the urine (<0.5% of dose) and feces (14% of the dose). [¹⁴C]MK-0767 was the major circulating compound-related entity (>96% of radioactivity) through 48 h postdose. It was also found that 91% of the total radioactivity area under the curve was due to intact MK-0767. Several minor metabolites were detected in plasma (<1% of radioactivity, each), formed by cleavage of the TZD ring and subsequent S-methylation and oxidation. All the metabolites excreted into urine were formed by TZD cleavage, whereas the major metabolite in feces was the O-demethylated derivative of MK-0767.

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