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

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 [C]MK-0767 were evaluated in six human volunteers after a 5-mg (200 Ci) oral dose. Excretion of C radioactivity was found to be nearly equal into the urine ( 50%) and feces ( 40%). Elimination of [C]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). [C]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. MK-0767 (2-methoxy-5-(2,4-dioxo-5-thiazolidinyl)-N-[[4-(trifluoromethyl)phenyl] methyl]benzamide, Fig. 1), also known as KRP297, is a thiazolidinedione (TZD)-containing compound that has been studied for the treatment of type 2 diabetes (Ballaux et al., 2006). In the same structural class as rosiglitazone and pioglitazone, MK-0767 is distinctly different from these compounds in that it binds to both and subtypes of the peroxisome proliferator-activated receptor (PPAR) with similar affinity (Murakami et al., 1998; Doebber et al., 2004), whereas rosiglitazone and pioglitazone were reported to bind primarily to the PPARreceptor (Lehmann et al., 1995; Forman et al., 1997). Binding to PPARand results in increased expression of genes encoding proteins involved in glucose and lipid metabolism (Mudaliar and Henry, 2001). The purpose of the present study was to investigate the absorption, metabolism, and excretion of [C]MK-0767 in six male human volunteers. The in vitro metabolism of MK-0767 in nonclinical species and humans has been described previously (Karanam et al., 2004a,b; Liu et al., 2004; Reddy et al., 2004), whereas the in vivo metabolism in nonclinical species is the subject of a separate manuscript in preparation (S. Vincent, C. Kochansky, M. Creighton, G. Doss, B. Karanam, M. Wallace, C. Raab, H. Jenkins, R. Franklin, S. Chiu, H. Satoh, K. Awano, and M. Komuro, unpublished). The main biotransformation pathway of MK-0767 in human liver microsomes involves CYP3A4-mediated oxidative cleavage of the TZD ring, followed by S-methylation (catalyzed primarily by microsomal methyltransferase) to the methyl mercapto metabolite (M25) and subsequent S-oxidation (catalyzed by both CYP3A and flavin-containing monooxygenase) to methyl sulfoxide and sulfone amides (M16 and M20, respectively). In hepatocytes, M16, M20, and M25 are subject to esterase-mediated hydrolysis to the carboxylic acid analogs (Liu et al., 2004). Materials and Methods Chemicals. MK-0767 was synthesized as the free acid by Kyorin Pharmaceuticals Co. (Tokyo, Japan). [Benzamide-C]MK-0767 (specific activity 40 Ci/mg) was synthesized by the Labeled Compound Synthesis Group (Merck Research Laboratories, Rahway, NJ) with 99.3% radiochemical purity (HPLC). [C]MK-0767 was formulated as a 0.25 mg/ml solution in 10% sulfobutyl ether cyclodextrin (Captisol) and 5% glycerol in 5 mM Tris buffer, pH 8.3, and stored at 20°C until administered. Dose Administration. A single oral dose of 5 mg (200 Ci) of [C]MK0767 was administered to six healthy, young male volunteers, 18 to 45 years old, by the Clinical Pharmacology Associates in Miami, FL. Dosing syringes were filled with 20 ml of dosing solution (5 mg of MK-0767) and weighed, and Article, publication date, and citation information can be found at http://dmd.aspetjournals.org. doi:10.1124/dmd.106.010231. ABBREVIATIONS: MK-0767, ( )-5-[2,4-dioxothiazol-5-yl)methyl]-2-methoxy-N-[4-trifluoromethyl] benzamide; HPLC, high-performance liquid chromatography; LC-MS/MS, liquid chromatography-tandem mass spectrometry; AUC, area under the curve; PPAR, peroxisome proliferatoractivated receptor; TZD, thiazolidinedione. 0090-9556/06/3409-1457–1461$20.00 DRUG METABOLISM AND DISPOSITION Vol. 34, No. 9 Copyright © 2006 by The American Society for Pharmacology and Experimental Therapeutics 10231/3132024 DMD 34:1457–1461, 2006 Printed in U.S.A. 1457 at A PE T Jornals on Jne 1, 2017 dm d.aspurnals.org D ow nladed from