(R)-, (S)-, and racemic fluoxetine N-demethylation by human cytochrome P450 enzymes.
Article Details
- CitationCopy to clipboard
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
Drug Enzyme Kind Organism Pharmacological Action Actions Fluoxetine Cytochrome P450 1A2 Protein Humans UnknownSubstrateInhibitorDetails Fluoxetine Cytochrome P450 2B6 Protein Humans UnknownSubstrateDetails Fluoxetine Cytochrome P450 2C19 Protein Humans UnknownSubstrateInhibitorDetails Fluoxetine Cytochrome P450 2C9 Protein Humans UnknownSubstrateInhibitorDetails Fluoxetine Cytochrome P450 2D6 Protein Humans NoSubstrateInhibitorDetails Fluoxetine Cytochrome P450 3A4 Protein Humans NoSubstrateInhibitorDetails Fluoxetine Cytochrome P450 3A5 Protein Humans UnknownSubstrateDetails - Drug Reactions
Reaction Details Details Details Details Details Details - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareFluoxetinePeginterferon alfa-2b The serum concentration of Fluoxetine can be decreased when it is combined with Peginterferon alfa-2b.
