Effects of chronic treatment with the leukotriene D4 antagonist compound LY171883 on Fischer 344 rats and rhesus monkeys.
One-year toxicity studies were done to evaluate potential toxic effects associated with chronic exposure of rats and monkeys to the leukotriene antagonist LY171883. Rats were fed dietary doses of 0.0, 0.01, 0.03, or 0.1%, equivalent to approximately 0, 5, 15, or 50 mg/kg of body weight/day. Monkeys were given daily nasogastric gavage doses of 0, 30, 75, or 175 mg/kg of body weight. No treatment-related effects occurred in physical, behavioral, ocular, food consumption, or urinalysis parameters in either species. Mild dose-related hepatotoxicity occurred in rats given approximately 15 or 50 mg/kg of LY171883. The hepatotoxicity was characterized by liver enlargement associated with induction of hepatic peroxisomal beta-oxidation and microsomal drug metabolism. Male rats also had hepatocellular fatty change, centrilobular hypertrophy of hepatocytes, and increased levels of serum alanine transaminase and total bilirubin. Other effects in rats included minimal decreases in hematocrit values, decreases in serum triglycerides and cholesterol, and increased kidney weight. The monkeys tolerated daily oral doses of LY171883 up to 175 mg/kg with only minor increases in hepatic microsomal enzyme activity and slightly increased liver and kidney weights in males. No effects occurred in monkeys given 30 mg/kg. There was no induction of hepatic peroxisomal enzymes or pathologic abnormalities in monkeys treated with LY171883. The peroxisomal inductive effect was apparently a species-related effect separate from the pharmacologic activity of leukotriene antagonism.
Hoover
D M
DM
Toxicology Division, Lilly Research Laboratories, Eli Lilly and Company, Greenfield, Indiana 46140.
Bendele
A M
AM
Hoffman
W P
WP
Foxworthy
P S
PS
Eacho
P I
PI
D000098:Acetophenones / Q000633:toxicity*; D000818:Animals; D001393:Azoles / Q000633:toxicity*; D005260:Female; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008253:Macaca mulatta; D008297:Male; D008830:Microbodies / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D013189:SRS-A / Q000037:antagonists & inhibitors*; D013045:Species Specificity; D013777:Tetrazoles / Q000633:toxicity*
D000098:Acetophenones; D001393:Azoles; D013189:SRS-A; D013777:Tetrazoles; C044660:LY 171883