Induction of hepatic drug-metabolizing enzymes in rats, dogs, and monkeys after repeated administration of an anti-inflammatory hexahydroindazole.

Abstract

The effect of repeated administration of an anti-inflammatory hexahydroindazole, (+/-)-3,3 alpha,4,5,6,7-hexahydro-2-[3-(4-morpholinyl)-propyl]-3-phenyl-7-(phenylmethylene)-2H-indazole (HMPPI), on hepatic microsomal drug-metabolizing enzymes in rats, dogs and monkeys was studied. Dose-dependent increases in the ratio of liver weight to body weight were observed in all three species. Microsomal protein concentration increased in rats and monkeys but not in dogs. Cytochrome P-450 concentration and aminopyrine N-demethylase activity increased in all species. Aniline hydroxylase activity increased only in dogs. In all three species, the largest increase in all parameters, except for the liver weight/body weight ratio, was observed in animals on the intermediate dose (50 mg/kg per d) of the hexahydroindazole, probably of the toxicity of the hexahydroindazole at the high dose (250 mg/kg per d).