Inhibition of leukotriene biosynthesis in the rat peritoneal cavity.
In the search for a model of leukotriene (LT) production to provide a method to determine in vivo 5-lipoxygenase (5-LO) inhibitory activity by various compounds, a passive anaphylactic reaction in the rat peritoneal cavity was examined, refined and characterized. The reaction, produced by passive sensitization with an i.p. injection of rabbit anti-bovine serum albumin (anti-BSA) followed by an i.p. injection of BSA, resulted in the biosynthesis of large amounts of sulfidopeptide LTs measurable by immunoassay or by reversed phase high performance liquid chromatography. The oral activity of several 5-LO inhibitors has been examined using this model. An example of these is zileuton (Abbott-64077), a potent 5-lipoxygenase inhibitor now under clinical evaluation. Zileuton inhibited sulfidopeptide LT biosynthesis in the rat peritoneal cavity in a dose-dependent manner (ED50 = 3 mg/kg). WY-49,232, MK-866, BW A4C and phenidone also produced good activity with ED50 values of 6, 8, 11 and 17 mg/kg, respectively. This modified rat peritoneal anaphylaxis model appears to be a valuable tool for establishing in vivo activity of 5-LO inhibitors.
Young
P R
PR
Immunosciences Research Area, Abbott Laboratories, Abbott Park, IL 60064.
Bell
R L
RL
Lanni
C
C
Summers
J B
JB
Brooks
D W
DW
Carter
G W
GW
D000284:Administration, Oral; D000707:Anaphylaxis / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology; D015289:Leukotrienes / Q000096:biosynthesis*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D010529:Peritoneal Cavity / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D013189:SRS-A / Q000096:biosynthesis
D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D013189:SRS-A; C063449:zileuton; D006918:Hydroxyurea