Absorption, Metabolism, and Excretion of [C]MK-0524, a Prostaglandin D2 Receptor Antagonist, in Humans

[(3R)-4-(4-Chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4tetrahydrocyclopentaindol-3-yl]acetic acid (MK-0524) is a potent orally active human prostaglandin D2 receptor 1 antagonist that is currently under development for the prevention of niacin-induced flushing. The metabolism and excretion of [C]MK-0524 in humans were investigated in six healthy human volunteers following a single p.o. dose of 40 mg (202 Ci). [C]MK-0524 was absorbed rapidly, with plasma Cmax achieved 1 to 1.5 h postdose. The major route of excretion of radioactivity was via the feces, with 68% of the administered dose recovered in feces. Urinary excretion averaged 22% of the administered dose, for a total excretion recovery of 90%. The majority of the dose was excreted within 96 h following dosing. Parent compound was the primary radioactive component circulating in plasma, comprising 42 to 72% of the total radioactivity in plasma for up to 12 h. The only other radioactive component detected in plasma was M2, the acyl glucuronic acid conjugate of the parent compound. The major radioactive component in urine was M2, representing 64% of the total radioactivity. Minor metabolites included hydroxylated epimers (M1/M4) and their glucuronic acid conjugates, which occurred in the urine as urea adducts, formed presumably during storage of samples. Fecal radioactivity profiles mainly comprised the parent compound, originating from unabsorbed parent and/or hydrolyzed glucuronic acid conjugate of the parent compound. Therefore, in humans, MK0524 was eliminated primarily via metabolism to the acyl glucuronic acid conjugate, followed by excretion of the conjugate into bile and eventually into feces. MK-0524 (Fig. 1) is a selective antagonist of prostaglandin D2 receptor 1 (DP1) (Sturino et al., 2007) that is undergoing preclinical and clinical development for the treatment of niacin-induced flushing. Niacin (nicotinic acid), a member of the vitamin B complex, has been used as a dietary supplement in milligram quantities and as a successful plasma lipid-modifying agent when administered in gram quantities. Niacin decreases plasma concentrations of cholesterol, free fatty acids, and triglycerides in humans, increases plasma high-density lipoprotein cholesterol (Shepherd et al., 1979), and decreases plasma very low-density lipoprotein and low-density lipoprotein cholesterol (Knopp, 1999). Furthermore, studies have shown that niacin can be effectively combined with statins to treat patients with low highdensity lipoprotein cholesterol (Rubenfire, 2004; Zhao et al., 2004). The major side effect with niacin therapy is the mild to severe cutaneous flushing experienced by patients that is mediated by vasodilation (Vogt et al., 2006). MK-0524, a potent DP1 antagonist, has an IC50 value of 1.1 nM in a mouse DP1 functional assay (C. Sturino, G. O’Neil, N. Lachance, M. Boyd, C. Berthelette, M. Labelle, L. Li, B. Roy, J. Scheigetz, and N. Tsou, unpublished results) and has been shown to block niacin-induced vasodilation in the mouse by 80% (Cheng et al., 2006). Furthermore, clinical studies have shown the efficacy of MK-0524 in attenuating niacin-induced vasodilation/flushing (Cheng et al., 2006). The objective of the present study is to investigate the absorption, metabolism, and excretion of [C]MK-0524 in six male human volunteers. In preclinical species (rats and dogs), MK-0524 was eliminated primarily via glucuronidation, followed by excretion of the acyl glucuronic acid conjugate of the parent compound (M2) in bile (Chang et al., 2007). The in vitro metabolism of MK-0524 in nonclinical species and humans has been described elsewhere (Dean et al., 2007). The major metabolite in hepatocytes from all the species was M2, whereas phase I metabolites (hydroxylated and keto derivatives) collectively comprised a minor component of the metabolic profiles (Dean et al., 2007). Materials and Methods Chemicals. MK-0524 was synthesized by Process Research at Merck Research Laboratories (Rahway, NJ). [C]MK-0524 (specific activity of 5 Article, publication date, and citation information can be found at http://dmd.aspetjournals.org. doi:10.1124/dmd.107.014696. ABBREVIATIONS: MK-0524, [(3R)-4-(4-chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopentaindol-3-yl]acetic acid; DP1, prostaglandin D2 receptor 1; HPLC, high-performance liquid chromatography; MS/MS, tandem mass spectrometry; LC/MS, liquid chromatography/ mass spectrometry; RP, reversed phase; AUC, area under the curve. 0090-9556/07/3507-1196–1202$20.00 DRUG METABOLISM AND DISPOSITION Vol. 35, No. 7 Copyright © 2007 by The American Society for Pharmacology and Experimental Therapeutics 14696/3219806 DMD 35:1196–1202, 2007 Printed in U.S.A. 1196 at A PE T Jornals on Sptem er 8, 2017 dm d.aspurnals.org D ow nladed from