Effect of Zileuton (A-64077) on the 5-lipoxygenase activity of human whole blood ex vivo.
The potency and reversibility of a new orally active 5-lipoxygenase (5-LO) inhibitor were evaluated in human volunteers. Zileuton (A-64077) 600 mg q.i.d. was administered to volunteers for 14 days in a phase I study, and blood samples were withdrawn, stimulated with ionophore A23187 and LTB4 levels were determined using both reverse phase high performance liquid chromatography (RP-HPLC) and radioimmunoassay (RIA). The drug significantly inhibited (above 70%) LTB4 biosynthesis in whole blood stimulated with A-23187 throughout the 14 days. The activity of 5-LO was also measured one week after stopping the medication and was returned to control levels. Measurement of LTB4 levels using either RP-HPLC or RIA gave similar percentage of inhibition although RIA appeared to underestimate by half the absolute amounts of LTB4 in the blood samples. These results show that Zileuton is a highly active and reversible 5-LO inhibitor in human.
Sirois
P
P
Department of Pharmacology, Faculty of Medicine, University of Sherbrooke, P.Q., Canada.
Borgeat
P
P
Lauzière
M
M
Dubé
L
L
Rubin
P
P
Kesterson
J
J
D000293:Adolescent; D000328:Adult; D001094:Arachidonate 5-Lipoxygenase / Q000097:blood*; D000001:Calcimycin / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004311:Double-Blind Method; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000494:pharmacology; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000097:blood; D016859:Lipoxygenase Inhibitors / Q000097:blood / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D011863:Radioimmunoassay
D016859:Lipoxygenase Inhibitors; D007975:Leukotriene B4; D000001:Calcimycin; D001094:Arachidonate 5-Lipoxygenase; C063449:zileuton; D006918:Hydroxyurea