Metabolism of lofepramine by rat liver microsomes

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Abstract
1. The metabolism of lofepramine† in vitro by rat liver microsomes was studied. The enzyme system involved was dependent on cytochrome P-450 and the main metabolites were desmethylimipramine (DMI), formaldehyde and p-chlorobenzoic acid. 2. Microsomes from rats pretreated with phenobarbital or 3-methylcholanthrene showed enhanced lofepramine metabolizing activity. The induction was reflected in increased Vmax values, whereas Km values were not changed. 3. Pretreatment of rats with lofepramine or DMI did not alter the rate of aniline hydroxylation, aminopyrine demethylation or lofepramine metabolism per mg microsomal protein. Nor was the amount of cytochrome P-450 changed. 4. Lofepramine, imipramine and DMI inhibited competitively the microsomal hydroxylation of aniline in vitro. Lofepramine was the most potent inhibitor, which probably reflects the higher lipophilicity of this compound.