title: Pharmacology of the 5-lipoxygenase inhibitors BAY Y 1015 and BAY X 1005 in the horse.
abstract: Calcium ionophore A23187 induced time and concentration dependent production of immunoreactive leukotriene (LT) B4 by equine heparinized whole blood in vitro. Time dependent production of immunoreactive LTB4 by equine neutrophils and immunoreactive LTC4 by equine eosinophils in vitro was also demonstrated. The 5-lipoxygenase activating protein (FLAP) inhibitors, BAY X 1005 and BAY Y 1015, produced concentration dependent inhibition of ionophore-induced LTB4 synthesis by equine whole blood (mean +/- SEM IC50s n = 5; 6.14 +/- 0.28 microM vs. 12.30 +/- 0.75 microM for BAY Y 1015 and BAY X 1005, respectively) and neutrophils (mean +/- SEM IC50s n = 5; 0.003 +/- 0.001 microM vs. 0.045 +/- 0.021 microM for BAY Y 1015 and BAY X 1005, respectively) and LTC4 synthesis by equine eosinophils (mean +/- SEM IC50s n = 5; 0.0036 +/- 0.0002 microM and 0.108 +/- 0.023 microM for BAY Y 1015 and BAY X 1005, respectively) in vitro. In all three assays, BAY Y 1015 was more potent than BAY X 1005, and for both compounds much higher concentrations were required to inhibit LT synthesis by whole blood compared to isolated neutrophils and eosinophils. Plasma concentration-time relationships and pharmacokinetic parameters for BAY Y 1015 administered intravenously and orally to six horses at a dosage of 10 mg/kg in a two period cross-over study were established. The study also evaluated the anti-inflammatory properties of BAY Y 1015 and its ability to inhibit ex vivo whole blood LTB4 synthesis and in vivo LTB4 synthesis in a tissue cage model of acute inflammation. At this dosage, BAY Y 1015 failed to significantly inhibit immunoreactive LTB4 synthesis or the oedema produced by intradermal injection of the mild irritant, carrageenan.
authors.affiliation: Department of Veterinary Basic Sciences, The Royal Veterinary College, Hawkshead Campus, North Mymms, Hertfordshire, UK.
authors.forename: F M
authors.initials: FM
authors.lastname: Cunningham
authors.forename: M
authors.initials: M
authors.lastname: Andrews
authors.forename: M F
authors.initials: MF
authors.lastname: Landoni
authors.forename: P
authors.initials: P
authors.lastname: Lees
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000001:Calcimycin; D002351:Carrageenan; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism; D005122:Exudates and Transudates / Q000276:immunology / Q000378:metabolism; D005260:Female; D006736:Horses / Q000097:blood / Q000378:metabolism*; D007275:Injections, Intravenous / Q000662:veterinary; D007975:Leukotriene B4 / Q000096:biosynthesis; D017997:Leukotriene C4 / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D011804:Quinolines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: C099016:Bay y 1015; D016859:Lipoxygenase Inhibitors; D011804:Quinolines; C079315:2-(4-(quinolin-2-yl-methoxy)phenyl)-2-cyclopentylacetic acid; D007975:Leukotriene B4; D017997:Leukotriene C4; D000001:Calcimycin; D002351:Carrageenan