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Abstract
1. Imipramine and its oxidized metabolites 2-hydroxyimipramine, desmethylimipramine (DMI), 2-hydroxydesmethylimipramine (2-OH-DMI), didesmethylimipramine (DDMI) and iminodibenzyl (IDB) all interact with cytochrome P-450 to give rise to the type I spectral change when added to suspensions of rat liver microsomes.
2. Imipramine, DMI and the more polar 2-OH-DMI, all exhibit high affinities for binding to the cytochrome.
3. The magnitude of the type I spectral change produced by imipramine is not enhanced by the further addition of DMI, neither is the DMI-induced type I spectral change increased by 2-OH-DMI. Thus it appears that imipramine and its oxidized metabolites interact with a common cytochrome P-450 species and that the inhibitory effect of DMI and 2-OH-DMI on the oxidation of imipramine and DMI, respectively, may be due to competition for binding to cytochrome P-450.
4. At low concentrations DDMI elicits a type I spectral change with microsomes but with increased concentration produces a type II spectral change. Similarly, DDMI even at low concentrations produces a type II spectral change with microsomes previously saturated with DMI. These findings suggest that DDMI can interact with cytochrome P-450 in more than one way.