ASSESSMENT OF THE IN-VIVO BIOCHEMICAL EFFICACY OF ORALLY-ACTIVE LEUKOTRIENE BIOSYNTHESIS INHIBITORS

In man, the therapeutic effectiveness of specific inhibitors of leukot riene (LT) biosynthsis against allergen-induced bronchoconstriction ap pears to be related to the in vivo biochemical efficacy of these compo unds, as measured by inhibition of whole blood LTB4 generation (upon A 23187 stimulus) and, particularly, urinary LTE4 excretion. Accordingly , we have assessed the ability of two clinically documented LT biosyth esis inhibitors, zileuton and MK-886, and the structurally novel 5-lip oxygenase activatig protein antagonist, MK-0591, to inhibit the produc tion of these inflammatory arachidonic acid metabolites in laboratory dogs. Zileuton (2 mg/kg) was extremely bioavailable in dogs (> 10 muM plasma concentrations), and inhibited the A23187-induced ex vivo produ ction of LTB4 by venous blood by > 90 %, in concordance with its poten cy in canine blood in vitro (IC50 = 1.1 muM). Despite this degree of i nhibition in whole blood, urinary LTE4 excretion was reduced by only 5 2 %, a profile of activity similar to that seen in clinical studies. M K-886 was less well absorbed, with plasma concentrations of 3 muM bein g achieved only at 25 mg/kg. These levels resulted in < 45 % inhibitio n of LTB, production, but a significant (p < 0.05) 47 % inhibition of urinary LTE4 excretion. MK-0591 was similarly bioavailable (compared w ith MK-886), but 10-fold more active in vivo as a 2 mg/kg dose resulte d in 41-62 % inhibition of urinary LTE, excretion (p < 0.05 vs control s; n = 4, 28). Significant inhibition of ex vivo LTB4 synthesis was al so observed at this dose (49 %), in accord with peak plasma concentrat ions of 0.5 muM and an in vitro potency of 0.2 - 0.4 muM (IC50) in who le blood from these animals. At higher dose (10 mg/kg), MK-0591 inhibi ted LTE4 excretion by 69 %, with 88 % inhibition of the LT biosyntheti c capacity of whole blood. These data demonstrate that the biochemical efficacy of structurally diverse leukotriene biosynthesis inhibitors can be assessed in vivo in normal laboratory dogs. Such measurements, combined with bioavailability data from other species, may be useful f or predicting biochemical activity in man.