title: Pharmacokinetics, pharmacodynamics, and safety of a prostaglandin D2 receptor antagonist.
abstract: Laropiprant is a selective antagonist of the prostaglandin D(2) (PGD(2)) receptor subtype 1 (DP1). Three double-blind, randomized, placebo-controlled studies evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple oral doses of laropiprant in healthy male volunteers. Single doses up to 900 mg and multiple doses up to 450 mg were generally well tolerated. Laropiprant exhibited dose-proportional pharmacokinetics. Oral absorption is rapid (T(max)=0.8-2.0 h) and the terminal half-life is approximately 12-18 h. The pharmacokinetics of laropiprant was not affected by food. Single doses of 6 mg and higher were effective in suppressing PGD(2)-induced cyclic AMP accumulation in platelets, demonstrating laropiprant target engagement with DP1. Laropiprant has detectable off-target antagonist effects at the thromboxane A(2) receptor but no clinically significant effect on collagen-induced platelet aggregation or bleeding times with multiple doses up to 200 mg.
authors: Merck Research Laboratories, Rahway, New Jersey and West Point, Pennsylvania, USA. eseng_lai@merck.com
authors: E
authors: E
authors: Lai
authors: L A
authors: LA
authors: Wenning
authors: T M
authors: TM
authors: Crumley
authors: I
authors: I
authors: De Lepeleire
authors: F
authors: F
authors: Liu
authors: J N
authors: JN
authors: de Hoon
authors: A
authors: A
authors: Van Hecken
authors: M
authors: M
authors: Depré
authors: D
authors: D
authors: Hilliard
authors: H
authors: H
authors: Greenberg
authors: G
authors: G
authors: O'Neill
authors: K
authors: K
authors: Metters
authors: K G
authors: KG
authors: Gottesdiener
authors: J A
authors: JA
authors: Wagner
mesh_terms: D000328:Adult; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006261:Headache / Q000097:blood / Q000139:chemically induced; D006801:Humans; D007211:Indoles / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D007211:Indoles; C518174:MK-0524; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C036293:prostaglandin D2 receptor