LEUKOTRIENE GENERATION AND METABOLISM IN DOGS - INHIBITION OF BIOSYNTHESIS BY MK-0591

Peptidoleukotriene metabolism in dogs was investigated to determine th e suitability of this species for the development of in vivo biochemic al models of asthma and inflammation. Circulatory metabolism of [H-3]l eukotriene (LT)C4 (0.5 muCi/kg, i.V.) to [H-3] LTE4 and subsequent cle arance was rapid (T 1/2 = 1 00 sec). After 3 h, the major urinary meta bolite was [H-3]16-carboxydihydrotetranor LTE4 (identified by radiochr omatography), with [H-3]LTE4 accruing to a significant 1.7 +/- 0.9% (n = 3) of the original [H-3] LTC4 dose. Immunoreactive LTE4 was excrete d into canine urine at 1.85 +/- 0.35 to 2.35 +/- 0.57 ng/h (n = 4) ove r a 6-h period, suggesting that this metabolite may be an index of acu te in vivo 5-lipoxygenase activity. MK-0591, a high-affinity ligand fo r the canine homolog of the human 5-lipoxygenase activating protein, d ose-dependently inhibited the systemic generation of peptidoleukotrien es as measured by urinary LTE4 excretion (ED50 1 mug/kg/min), the time course of disappearance of LTE4 from the urine being similar to that of the clearance of [H-3]LTE4. Because the therapeutic improvements in human allergic asthmatics treated with LT synthesis inhibitors and ch allenged with antigen appear to be related to the degree of in vivo in hibition of LT biosynthesis (measured by urinary LTE4), the dog may be an appropriate species for preclinical assessment of LT inhibitors.