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Inhibition of synovial LTB 4 production by a specific leukotriene biosynthesis inhibitor, MK‐0591, in a rabbit model of joint inflammation
Author(s) -
Brideau Christine,
Chan ChiChung,
Guevremont Diane,
Hutchinson John H.,
McDonnell Joseph,
Moore Ver
Publication year - 1993
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430290304
Subject(s) - leukotriene b4 , chemistry , leukotriene , in vivo , biosynthesis , inflammation , medicine , leukotriene c4 , endogeny , pharmacology , endocrinology , immunology , enzyme , biochemistry , biology , microbiology and biotechnology , asthma
The effect of a leukotriene biosynthesis inhibitor (MK‐0591) on LTB 4 synthesis was examined in a rabbit model of joint inflammation. Intra‐articular (ia) injection of human recombinant interleukin‐1β (rlL‐1β, 50–400 ng/joint) resulted in dose‐dependent infiltration of leukocytes into the synovium but produced only background levels of LTB 4 over a time course of 14–16 h, suggesting that the leukocytes were not activated with respect to LTB 4 metabolism. The influx of leukocytes in the synovial space was not inhibited by MK‐0591. Injection of A23187 (100 nmol/joint, ia) in addition to rlL‐1β elicited significant LTB 4 release in the synovial fluid. MK‐0591 given iv 30 min before A23187 significantly inhibited the release of LTB 4 (ED 50 = 0.3 mg/kg), without affecting the number of leukocytes in the synovium. In rabbit whole blood challenged with A23187 in vitro, MK‐0591 also potently inhibited LTB 4 synthesis (IC 50 = 126 ± 29 nM). The in vivo inhibitory action of MK‐0591 was in good agreement with the plasma levels of the compound (0.62 μM in the group treated with MK‐0591 at 3 mg/kg) and its biochemical efficacy in vitro (100% inhibition of LTB 4 synthesis). The effect of MK‐0591 was comparable to that of another leukotriene biosynthesis inhibitor, MK‐886. Indomethacin at dose up to 3 mg/kg iv did not affect the production of LTB 4 in the joint. The present study demonstrates that MK‐0591 inhibits LTB 4 biosynthesis with high potency in the rabbit synovium, a microenvironment rich in protein and leukocytes. It would be of interest to determine whether such an action would be beneficial in the management of rheumatoid arthritis or other inflammatory conditions in humans. ©1993 Wiley‐Liss, Inc.