SUBCHRONIC TOXICITY STUDIES WITH THE LEUKOTRIENE D-4 ANTAGONIST RG-12525

Preclinical safety studies with the leukotriene D-4 antagonist RG 1252 5 were conducted by the oral route in mice, rats, and monkeys, Oral ad ministration of RG 12525 was repeated daily in studies up to 6 months in duration, RG 12525 was shown to have limited high-dose toxicity aft er repeated oral administration. The effects of RG 12525 were strongly dependent upon the species considered, High doses of RG 12525 caused significant increases in liver weight in mice, rats, and monkeys that were associated with diffuse hepatocellular hypertrophy in mice and ra ts but not in monkeys, No related clinical chemistry changes were obse rved in any of the species and hepatic activities of peroxisomal enzym es or cytochrome P450 were increased only slightly. Proliferation of b rown adipose tissue (BAT) was observed in rats and mice but not in mon keys. The BAT reaction was more pronounced in the interscapular area b ut it was also observed in other subcutaneous locations as well as in mediastinal and bone marrow fat. In all locations, the RG 12525-induce d BAT had some morphological similarities with cold-adapted BAT. Repea ted administration of RG 12525 at high doses to female rats resulted i n a lack of progression to the luteal phase of the estrous cycle that was reversible after discontinuation of treatment. Finally, RG 12525 w as nephrotoxic in mice with males being more sensitive than females. ( C) 1995 Society of Toxicology