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First published on June 13, 2006; DOI: 10.1124/dmd.106.010231

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Received for publication March 23, 2006.
Revised May 31, 2006.
Accepted for publication May 31, 2006.

Absorption, Metabolism, and Excretion of [14C]MK-0767 in Humans

Christopher J. Kochansky 1*, Ronda Rippley 2, Kerri Yan 3, Hengchang Song 2, Michael Wallace 2, Dennis Dean 2, Allen Jones 2, Kenneth Lasseter 4, Jules Schwartz 1, Stella H Vincent 3, Ronald B. Franklin 5, John A. Wagner 1

1 Merck Research Labs 2 Merck Research Laboratories 3 Merck 4 Clinical Pharmacology Associates 5 Array BioPharma

* Address correspondence to: E-mail: christopher_kochansky{at}merck.com

Abstract

MK-0767 (KRP-297) 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 following 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 hr post-dose. It was also found that ~91% of the total radioactivity AUC 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, while the major metabolite in feces was the O-demethylated derivative of MK-0767.


Key words: absorption, excretion, human pharmacokinetics, peroxisome proliferator-activated receptors


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R. K. Rippley, K. X. Yan, N. D. Matthews, H. E. Greenberg, G. A. Herman, and J. A. Wagner
Human Pharmacokinetics and Interconversion of Enantiomers of MK-0767, a Dual PPAR{alpha}/{gamma} Agonist
J. Clin. Pharmacol., March 1, 2007; 47(3): 323 - 333.
[Abstract] [Full Text] [PDF]


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