Assessment of the in 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 the in 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 activating 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 microM plasma concentrations), and inhibited the A23187-induced ex vivo production of LTB4 by venous blood by > 90%, in concordance with its potency in canine blood in vitro (IC50 = 1.1 microM). 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 microM 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 active in 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 of ex vivo LTB4 synthesis was also observed at this dose (49%), in accord with peak plasma concentrations of 0.5 microM and an in vitro potency of 0.2-0.4 microM (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 assessed in vivo in normal laboratory dogs. Such measurements, combined with bioavailability data from other species, may be useful for predicting biochemical activity in man.
Tagari
P
P
Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, Pointe Claire-Dorval, Québec, Canada.
Brideau
C
C
Chan
C
C
Frenette
R
R
Black
C
C
Ford-Hutchinson
A
A
D000818:Animals; D000001:Calcimycin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003864:Depression, Chemical; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D007211:Indoles / Q000493:pharmacokinetics / Q000494:pharmacology; D020024:Leukotriene Antagonists; D017999:Leukotriene E4 / Q000096:biosynthesis / Q000097:blood / Q000652:urine; D015289:Leukotrienes / Q000096:biosynthesis*; D016859:Lipoxygenase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D011804:Quinolines / Q000493:pharmacokinetics / Q000494:pharmacology; D002722:Chlorobenzenes
D000001:Calcimycin; D006918:Hydroxyurea; D007211:Indoles; D020024:Leukotriene Antagonists; D017999:Leukotriene E4; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D011804:Quinolines; C060893:MK-886; D002722:Chlorobenzenes; C078266:MK 0591; C063449:zileuton