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

Abstract

1. The effect of repeated administration of an anti-inflammatory hexahydroindazole, (±)-3,3a,4, 5,6,7-hexahydro-2-[3-(4-morpholinyl)-propyl] -3-phenyl-7-(phenylmethyl-ene)-2H-indazole (HMPPI), on hepatic microsomal drug-metabolizing enzymes in rats, dogs and monkeys was studied.

2. Dose-dependent increases in the ratio of liver weight to body weight were observed in all three species.

3. 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.

4. 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 because of the toxicity of the hexahydroindazole at the high dose (250 mg/kg per d).