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.