Fuller R W, Snoddy H D
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285.
Res Commun Chem Pathol Pharmacol. 1991 Jul;73(1):31-40.
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.
氟西汀是一种血清素摄取抑制剂，已知它会抑制包括地昔帕明在内的一些药物的代谢，当这两种药物同时给大鼠服用时，会导致地昔帕明在大脑和血液中的水平升高。去甲氟西汀是氟西汀的N-去甲基代谢产物，在提高大鼠大脑和血液中地昔帕明水平方面，其效力比氟西汀弱。由于血清素摄取受到抑制，去甲氟西汀在降低大脑中5-羟吲哚乙酸（5-HIAA）浓度方面与氟西汀基本等效。给大鼠注射氟西汀后，在1小时时大脑中氟西汀的水平高于去甲氟西汀，但在更长时间（直至24小时），大脑（和肝脏）中去甲氟西汀的水平高于氟西汀。注射氟西汀后，大脑中5-HIAA的水平至少在24小时内降低，这显然是由于去甲氟西汀持续存在并抑制血清素摄取所致。在注射氟西汀16小时后注射地昔帕明，大脑中地昔帕明的水平不再升高。结果表明，去甲氟西汀在很大程度上导致了氟西汀给药后血清素摄取的抑制，但对抑制地昔帕明代谢的作用较小，甚至可能没有作用。
