The Induction Profile of Three Orally Active Imidazopyridine-Containing Cardiotonic Agents in Rat Hepatic Microsomes

Abstract

The Induction Profile of Three Orally Active Imidazopyridine-Containing Cardiotonic Agents in Rat Hepatic Microsomes. BERNSTEIN, J. R, AND FRANKLIN, R. B., (1986). Fundam Appl. Toxicol. 7, 26-32. 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[4,5-6]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 0-de- alkylation 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-c]pyndine-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 cy- tochrome-.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-1 containing compounds exhibited modified Type II difference spectra when added to a suspension of rat hepatic microsomes. The imidazo[4,5-6]pyridine-containing compound has previously been reported to be (i) a rapid and potent inducer of monooxygenase activity and (ii) have a Type II difference Spectrum.(c) 1986 Society of Toxicology