Role of norfluoxetine in the inhibition of desipramine metabolism and in the inhibition of serotonin uptake after fluoxetine administration to rats.

Fluoxetine, a serotonin uptake inhibitor, is known to inhibit the metabolism of some drugs including desipramine, resulting in increased brain and blood levels of desipramine when the drugs are co-administered to rats. Norfluoxetine, the N-desmethyl metabolite of fluoxetine, was found to be less potent than fluoxetine in increasing brain and blood levels of desipramine in rats. Norfluoxetine was essentially equipotent to fluoxetine in decreasing brain concentrations of 5-hydroxyindoleacetic acid (5-HIAA) as a consequence of serotonin uptake inhibition. After the injection of fluoxetine into rats, brain levels of fluoxetine predominated over those of norfluoxetine at 1 hour, but at longer times (out to 24 hours), norfluoxetine levels were higher in brain (and in liver) than fluoxetine levels. Brain levels of 5-HIAA were decreased for at least 24 hours after fluoxetine injection, due apparently to the persistence of and inhibition of serotonin uptake by norfluoxetine. When desipramine was injected 16 hrs after fluoxetine injection, brain levels of desipramine were no longer elevated. The results suggest that norfluoxetine contributes in a major way to the inhibition of serotonin uptake after fluoxetine administration but contributes less, if at all, to the inhibition of desipramine metabolism.