Chronic leukotriene inhibition in the rat fails to modify the toxicological effects of a cyclooxygenase inhibitor.
A 5-week study was carried out in rats using a leukotriene biosynthesis inhibitor (MK-886; 3-[1-(4-chlorobenzyl)-3-t-butylthio-5-isopropylindol-2-yl]-2,2- dimethylpropanoic acid) at a dose of 300 mg.kg-1 x day-1, this being sufficient to produce > 90% inhibition of ex vivo leukotriene B4 synthesis in rat blood, and a cyclooxygenase inhibitor (indomethacin, 4 and 6 mg.kg-1 x day-1) to ascertain whether inhibition of leukotriene biosynthesis would potentiate or inhibit the toxicity associated with the administration of nonsteroidal anti-inflammatory drugs (NSAIDs), in particular the gastrointestinal damage. Treatment with indomethacin alone or in combination with MK-886 resulted in the toxicity normally associated with NSAIDs, including gastrointestinal lesions. No toxicity was associated with the administration of MK-886 alone, and MK-886 had no significant effect on the incidence of gastrointestinal lesions produced by indomethacin. These results indicate that leukotrienes are not significant mediators of NSAID-induced gastroenteropathy in the rat.
Ford-Hutchinson
A W
AW
Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, Pointe-Claire-Dorval, Canada.
Tagari
P
P
Ching
S V
SV
Anderson
C A
CA
Coleman
J B
JB
Peter
C P
CP
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000633:toxicity*; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D007211:Indoles / Q000494:pharmacology*; D007213:Indomethacin / Q000633:toxicity*; D020024:Leukotriene Antagonists; D015289:Leukotrienes / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors / Q000633:toxicity; D008297:Male; D051381:Rats; D002722:Chlorobenzenes
D016718:Arachidonic Acid; D016861:Cyclooxygenase Inhibitors; D007211:Indoles; D007213:Indomethacin; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; C060893:MK-886; D002722:Chlorobenzenes