The induction profile of three orally active imidazopyridine-containing cardiotonic agents in rat hepatic microsomes.
The induction of hepatic cytochrome P-450-linked monooxygenases has been studied after the twice daily, oral administration of two imidazo[4,5-c]pyridine-containing compounds and one imidazo[4,5-b]pyridine-containing drug. The compounds were administered by the oral route, at different doses, for 6 days after which time hepatic microsomes were prepared. In vitro biochemical assays revealed that all three compounds increased the O-deethylation of 7-ethoxyresorufin in a dose-dependent manner while not significantly affecting either the O-dealkylation of 7-ethoxycoumarin or the levels of NADPH-cytochrome c reductase. Ethylmorphine N-demethylation was decreased after dosing with the imidazo[4,5-b]pyridine-containing drug. Levels of cytochrome(s) P-450 and liver-to-body weight ratios were not significantly altered. The imidazo[4,5-b]pyridine-containing compound was more potent in terms of the induction of 7-ethoxyresorufin than either of the imidazo[4,5-c]pyridine-containing compounds but was approximately fourfold less active in this regard than 3-methylcholanthrene. No induction of cytochrome-P-450-linked monooxygenase activities was evident at a twice daily dose of 5 mg/kg for 6 days for all three compounds tested, constituting a no-effect level. The imidazo[4,5-c]pyridine-containing compounds exhibited modified Type II difference spectra when added to a suspension of rat hepatic microsomes. The imidazo[4,5-b]pyridine-containing compound has previously been reported to be a rapid and potent inducer of monooxygenase activity and have a Type II difference spectrum.
D015660:7-Alkoxycoumarin O-Dealkylase; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D019363:Cytochrome P-450 CYP1A1; D004790:Enzyme Induction / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism*; D009251:NADPH-Ferrihemoprotein Reductase / Q000096:biosynthesis; D009929:Organ Size / Q000187:drug effects; D010088:Oxidoreductases / Q000096:biosynthesis; D010105:Oxygenases / Q000096:biosynthesis; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D002316:Cardiotonic Agents; D007093:Imidazoles; D008748:Methylcholanthrene; C046815:LY 163252; D010088:Oxidoreductases; D010105:Oxygenases; D015660:7-Alkoxycoumarin O-Dealkylase; D019363:Cytochrome P-450 CYP1A1; D009251:NADPH-Ferrihemoprotein Reductase; C029758:sulmazole; D010634:Phenobarbital