Induction of hepatic drug-metabolizing enzymes in rats, dogs, and monkeys after repeated administration of an anti-inflammatory hexahydroindazole.
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).
D000633:Aminopyrine N-Demethylase / Q000096:biosynthesis; D000815:Aniline Hydroxylase / Q000096:biosynthesis; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004285:Dogs; D004790:Enzyme Induction / Q000187:drug effects*; D005260:Female; D007191:Indazoles / Q000494:pharmacology*; D008253:Macaca mulatta; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D013045:Species Specificity
D000893:Anti-Inflammatory Agents; D007191:Indazoles; D011720:Pyrazoles; C039471:SQ 26298; D003577:Cytochrome P-450 Enzyme System; D000815:Aniline Hydroxylase; D000633:Aminopyrine N-Demethylase