Absorption, metabolism, and excretion of [14C]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 alpha and gamma 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 microCi) oral dose. Excretion of 14C radioactivity was found to be nearly equal into the urine (approximately 50%) and feces (approximately 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 (approximately 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 approximately 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.
Kochansky
Christopher J
CJ
Department of Drug Metabolism, Merck Research Laboratories, PA 19486, USA. christopher_kochansky@merck.com
Rippley
Ronda K
RK
Yan
Kerri X
KX
Song
Hengchang
H
Wallace
Michael A
MA
Dean
Dennis
D
Jones
Allen N
AN
Lasseter
Kenneth
K
Schwartz
Jules
J
Vincent
Stella H
SH
Franklin
Ronald B
RB
Wagner
John
J
D000042:Absorption; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D001711:Biotransformation; D002250:Carbon Radioisotopes; D005243:Feces / Q000737:chemistry; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000652:urine; D008297:Male; D008875:Middle Aged; D013844:Thiazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine
D002250:Carbon Radioisotopes; D007004:Hypoglycemic Agents; C487303:MK0767; D013844:Thiazoles