The pharmacokinetics and disposition of MK-0524, a Prostaglandin D₂ receptor 1 antagonist, in rats, dogs and monkeys

Abstract

MK-0524 is a potent, selective and orally active Prostaglandin D₂ receptor 1 (DP₁) 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 ∼2 and ∼6 ml/min/kg, the T_1/2 was ∼7 and ∼13 h and the Vd_ss was ∼1 and ∼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.

Key Words::

• MK-0524
• pharmacokinetics
• metabolism
• acyl glucuronide

Acknowledgements

The authors thank Dr Matt Braun, Dr Eric Soli and Ms Yuming Zhao for synthesis of [¹⁴C]MK-0524 and M2; Dr William Feeney, Ms Suzanne Ciccotto, Mr Chris Freeden, Mr Donald Hora and Mr Paul Cunningham for their support of the in vivo studies; Dr Maria Silva Elipe for NMR data on rearranged isomers of acyl glucuronide, and Dr Alana Upthagrove and Dr Stella Vincent for the rat mass balance data. The authors are grateful also to colleagues at Merck Frosst for conducting the monkey studies and to Dr Deborah Nicoll-Griffith for helpful discussions.

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