RT Journal Article
SR Electronic
T1 Absorption, Metabolism, and Excretion of [14C]MK-0524, a Prostaglandin D2 Receptor Antagonist, in Humans
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1196
OP 1202
DO 10.1124/dmd.107.014696
VO 35
IS 7
A1 Bindhu Karanam
A1 Maria Madeira
A1 Scott Bradley
A1 Larissa Wenning
A1 Rajesh Desai
A1 Eric Soli
A1 David Schenk
A1 Allen Jones
A1 Brian Dean
A1 George Doss
A1 Graigory Garrett
A1 Tami Crumley
A1 Ajay Nirula
A1 Eseng Lai
YR 2007
UL http://dmd.aspetjournals.org/content/35/7/1196.abstract
AB [(3R)-4-(4-Chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopentaindol-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 [14C]MK-0524 in humans were investigated in six healthy human volunteers following a single p.o. dose of 40 mg (202 μCi). [14C]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, MK-0524 was eliminated primarily via metabolism to the acyl glucuronic acid conjugate, followed by excretion of the conjugate into bile and eventually into feces. The American Society for Pharmacology and Experimental Therapeutics