The pharmacokinetics and disposition of MK-0524, a Prosglandin D2 Receptor 1 antagonist, in rats, dogs and monkeys.
MK-0524 is a potent, selective and orally active Prosglandin D(2) Receptor 1 (DP(1)) antagonist currently under clinical development for the treatment of niacin-induced flushing. Experiments to study the pharmacokinetics, metabolism and excretion of MK-0524 were conducted in rats, dogs and monkeys. MK-0524 displayed linear kinetics and rapid absorption following an oral dose. Following intravenous (i.v.) administration of MK-0524 to rats and dogs (1 and 5 mg/kg), the mean Cl(p) was approximately 2 and approximately 6 ml/min/kg, the T(1/2) was approximately 7 and approximately 13 h and the Vd(ss) was approximately 1 and approximately 5 L/kg, respectively. In monkeys dosed i.v. at 3 mg/kg, the corresponding values were 8 ml/min/kg, 3 h and 1 L/kg, respectively. Following oral dosing of MK-0524 to rats (5, 25 and 100 mg/kg), dogs (5 mg/kg) and monkeys (3 mg/kg), the absorption was rapid with the mean C(max) occurring between 1 and 4 h. Absolute oral bioavailability values in rats, dogs and monkeys were 50, 70 and 8%, respectively. The major circulating metabolite was the acyl glucuronide of MK-0524 (M2), with ratios of glucuronide to the parent aglycone being highest in the monkey followed by dog and rat. In bile duct-cannulated rats and dogs, MK-0524 was eliminated primarily via acyl glucuronidation followed by biliary excretion of the acyl glucuronide, M2, the major drug-related entity in bile.
Chang
S W
SW
Department of Drug Metabolism, Merck Research Laboratories, Rahway, New Jersey 07065 , USA.
Reddy
V
V
Pereira
T
T
Dean
B J
BJ
Xia
Y-Q
YQ
Seto
C
C
Franklin
R B
RB
Karanam
B V
BV
D000818:Animals; D001646:Bile / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004355:Drug Stability; D020719:Glucuronides / Q000097:blood / Q000493:pharmacokinetics; D006207:Half-Life; D000882:Haplorhini / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D013058:Mass Spectrometry; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*
D001798:Blood Proteins; D020719:Glucuronides; D007211:Indoles; C518174:MK-0524; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C036293:prostaglandin D2 receptor