Pharmacokinetics and pharmacodynamics of multiple oral doses of MK-0591, a 5-lipoxygenase-activating protein inhibitor.
The pharmacodynamics, kinetics, and tolerability of a new orally active 5-lipoxygenase inhibitor were evaluated in healthy male volunteers. MK-0591, 50, 125, and 250 mg every morning and 250 mg every 12 hours, was administered for 10 days. Leukotriene B4 biosynthesis ex vivo in ionophore (A23187)-stimulated whole blood and leukotriene E4 levels in urine were determined. Leukotriene B4 production was inhibited up to 90% of baseline for 12 hours after administration at the highest dose. The degree of leukotriene B4 inhibition ex vivo in whole blood significantly correlated with plasma MK-0591 concentrations (0 to 1500 ng/ml; r = 0.73). Urinary leukotriene E4 was inhibited by > 80% at 24 hours after administration for all dose levels. Pharmacokinetics of MK-0591 were linear, with a half-life of approximately 6 hours. Very little accumulation was seen after multiple dosing. MK-0591 had no effect on testosterone levels, and good tolerability was shown at all dose levels of MK-0591 administered for up to 10 days.
Department of Pharmacology, School of Medicine, Leuven, Belgium.
M
M
Depré
B
B
Friedman
A
A
Van Hecken
I
I
de Lepeleire
W
W
Tanaka
A
A
Dallob
S
S
Shingo
A
A
Porras
C
C
Lin
P J
PJ
de Schepper
D058927:5-Lipoxygenase-Activating Proteins; D000284:Administration, Oral; D000328:Adult; D000704:Analysis of Variance; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D004311:Double-Blind Method; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D020024:Leukotriene Antagonists; D007975:Leukotriene B4 / Q000097:blood / Q000652:urine; D016859:Lipoxygenase Inhibitors; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D012016:Reference Values; D012129:Respiratory Function Tests; D013739:Testosterone / Q000097:blood
D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D002352:Carrier Proteins; D007211:Indoles; D020024:Leukotriene Antagonists; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D011804:Quinolines; C078266:MK 0591; D007975:Leukotriene B4; D013739:Testosterone