Assessment of thein vivo biochemical efficacy of orally active leukotriene biosynthesis inhibitors

In man, the therapeutic effectiveness of specific inhibitors of leukotriene (LT) biosynthesis against allergen-induced bronchoconstriction appears to be related to thein vivo biochemical efficacy of these compounds, as measured by inhibition of whole blood LTB₄ generation (upon A23187 stimulus) and, particularly, urinary LTE₄ excretion. Accordingly, we have assessed the ability of two clinically documented LT biosynthesis inhibitors, zileuton and MK-886, and the structurally novel 5-lipoxygenase activatig protein antagonist, MK-0591, to inhibit the production of these inflammatory arachidonic acid metabolites in laboratory dogs. Zileuton (2 mg/kg) was extremely bioavailable in dogs (>10 M plasma concentrations), and inhibited the A23187-inducedex vivo production of LTB₄ by venous blood by >90%, in concordance with its potency in canine bloodin vitro (IC₅₀=1.1 M). Despite this degree of inhibition in whole blood, urinary LTE₄ excretion was reduced by only 52%, a profile of activity similar to that seen in clinical studies. MK-886 was less well absorbed, with plasma concentrations of 3 M being achieved only at 25 mg/kg. These levels resulted in <45% inhibition of LTB₄ production, but a significant (p<0.05) 47% inhibition of urinary LTE₄ excretion. MK-0591 was similarly bioavailable (compared with MK-886), but 10-fold more activein vivo as a 2 mg/kg dose resulted in 41–62% inhibition of urinary LTE₄ excretion (p<0.05 vs controls;n=4, 28). Significant inhibition ofex vivo LTB₄ synthesis was also observed at this dose (49%), in accord with peak plasma concentrations of 0.5 M and anin vitro potency of 0.2–0.4 M (IC₅₀) in whole blood from these animals. At higher dose (10 mg/kg), MK-0591 inhibited LTE₄ excretion by 69%, with 88% inhibition of the LT biosynthetic capacity of whole blood. These data demonstrate that the biochemical efficacy of structurally diverse leukotriene biosynthesis inhibitors can be assessedin vivo in normal laboratory dogs. Such measurements, combined with bioavailability data from other species, may be useful for predicting biochemical activity in man.