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Abstract
1. The in vitro metabolism of lofepramine was studied in comparison with imipramine. Both compounds were hydroxylated and demethylated by a NADPH-generating system in rat and human liver microsomes.
2. Three metabolites were in common for the two drugs, namely desipramine (DMI), 2-hydroxydesipramine (2-OH-DMI) and didesmethylimipramine (DDMI).
3. Lofepramine was also metabolized to three unique tricyclic metabolites. Comparisons with authentic reference compounds suggested that two of these metabolites were 2-hydroxylofepramine and desmethyllofepramine.
4. The ratio between the concentrations of DDMI and DMI was higher for lofepramine than imipramine. This is probably due to DDMI formation via two parallel metabolic pathways of lofepramine, i.e. DMI and desmethyllofepramine, respectively.
5. It is speculated that the different metabolic pattern of lofepramine as compared with desipramine and imipramine is of importance for the therapeutic profile of the drug.