(R)-, (S)-, and racemic fluoxetine N-demethylation by human cytochrome P450 enzymes.

Article Details

Citation

Margolis JM, O'Donnell JP, Mankowski DC, Ekins S, Obach RS

(R)-, (S)-, and racemic fluoxetine N-demethylation by human cytochrome P450 enzymes.

Drug Metab Dispos. 2000 Oct;28(10):1187-91.

PubMed ID
10997938 [ View in PubMed
]
Abstract

Fluoxetine is one of the most widely prescribed selective serotonin reuptake inhibitors (SSRIs) that is marketed worldwide. However, details of its human hepatic metabolism have been speculative and incomplete, possibly due to the sensitivity of analytical techniques and selectivity of specific in vitro probes and reagents used. Studies with (R)-, (S)-, and racemic fluoxetine were undertaken to determine the stereospecific nature of its metabolism and estimate intrinsic clearance contributions of each CYP for fluoxetine N-demethylation. Measurable fluoxetine N-demethylase activity was catalyzed by CYP1A2, -2B6, -2C9, -2C19, -2D6, -3A4, and -3A5. All enzymes catalyzed this reaction for both enantiomers and the racemate, and intrinsic clearance values were similar for the enantiomers for all CYP enzymes except CYP2C9, which demonstrated stereoselectivity for R- over the S-enantiomer. Scaling the intrinsic clearance values for the individual CYP enzymes to estimate contributions of each in human liver microsomes suggested that CYP2D6, CYP2C9, and CYP3A4 contribute the greatest amount of fluoxetine N-demethylation in human liver microsomes. These data were corroborated with the examination of the effects of CYP-specific inhibitors quinidine (CYP2D6), sulfaphenazole (CYP2C9), and ketoconazole (CYP3A4) on fluoxetine N-demethylation in pooled human liver microsomes. Together, these findings suggest a significant role for the polymorphically expressed CYP2D6 in fluoxetine clearance and are consistent with reports on the clinical pharmacokinetics of fluoxetine.

DrugBank Data that Cites this Article

Drugs
Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
FluoxetineCytochrome P450 1A2ProteinHumans
Unknown
Substrate
Inhibitor
Details
FluoxetineCytochrome P450 2B6ProteinHumans
Unknown
Substrate
Details
FluoxetineCytochrome P450 2C19ProteinHumans
Unknown
Substrate
Inhibitor
Details
FluoxetineCytochrome P450 2C9ProteinHumans
Unknown
Substrate
Inhibitor
Details
FluoxetineCytochrome P450 2D6ProteinHumans
No
Substrate
Inhibitor
Details
FluoxetineCytochrome P450 3A4ProteinHumans
No
Substrate
Inhibitor
Details
FluoxetineCytochrome P450 3A5ProteinHumans
Unknown
Substrate
Details
Drug Reactions
Reaction
Details
Details
Details
Details
Details
Details
Drug Interactions
DrugsInteraction
Fluoxetine
Peginterferon alfa-2b
The serum concentration of Fluoxetine can be decreased when it is combined with Peginterferon alfa-2b.
Identify potential medication risks
Easily compare up to 40 drugs with our drug interaction checker.
Get severity rating, description, and management advice.
Learn more