Leukotriene generation and metabolism in dogs: inhibition of biosynthesis by MK-0591.
Peptidoleukotriene metabolism in dogs was investigated to determine the suitability of this species for the development of in vivo biochemical models of asthma and inflammation. Circulatory metabolism of [3H]leukotriene (LT)C4 (0.5 microCi/kg, i.v.) to [3H]LTE4 and subsequent clearance was rapid (T1/2 = 100 sec). After 3 h, the major urinary metabolite was [3H]16-carboxydihydrotetranor LTE4 (identified by radiochromatography), with [3H]LTE4 accruing to a significant 1.7 +/- 0.9% (n = 3) of the original [3H]LTC4 dose. Immunoreactive LTE4 was excreted into canine urine at 1.85 +/- 0.35 to 2.35 +/- 0.57 ng/h (n = 4) over a 6-h period, suggesting that this metabolite may be an index of acute in vivo 5-lipoxygenase activity. MK-0591, a high-affinity ligand for the canine homolog of the human 5-lipoxygenase activating protein, dose-dependently inhibited the systemic generation of peptidoleukotrienes as measured by urinary LTE4 excretion (ED50 1 microgram/kg/min), the time course of disappearance of LTE4 from the urine being similar to that of the clearance of [3H]LTE4. Because the therapeutic improvements in human allergic asthmatics treated with LT synthesis inhibitors and challenged with antigen appear to be related to the degree of in vivo inhibition of LT biosynthesis (measured by urinary LTE4), the dog may be an appropriate species for preclinical assessment of LT inhibitors.
Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, Pointe Claire-Dorval, Quebec, Canada.
P
P
Tagari
A
A
Becker
C
C
Brideau
R
R
Frenette
V
V
Sadl
E
E
Thomas
P
P
Vickers
A
A
Ford-Hutchinson
D058927:5-Lipoxygenase-Activating Proteins; D000818:Animals; D001249:Asthma / Q000188:drug therapy; D002352:Carrier Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D020024:Leukotriene Antagonists; D017999:Leukotriene E4; D015289:Leukotrienes / Q000096:biosynthesis* / Q000378:metabolism / Q000652:urine; D008565:Membrane Proteins / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology* / Q000627:therapeutic use; D013189:SRS-A / Q000031:analogs & derivatives / Q000652:urine
D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D002352:Carrier Proteins; D007211:Indoles; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D008565:Membrane Proteins; D011804:Quinolines; D013189:SRS-A; C078266:MK 0591; D017999:Leukotriene E4