(R)-, (S)-, and racemic fluoxetine N-demethylation by human cytochrome P450 enzymes.
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.
Margolis
J M
JM
Drug Metabolism Department, Candidate Synthesis, Enhancement, and Evaluation, Central Research Division, Pfizer Inc., Groton, Connecticut, USA. vsevolod.kostrubsky@pfizer.com
O'Donnell
J P
JP
Mankowski
D C
DC
Ekins
S
S
Obach
R S
RS
D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology; D007700:Kinetics; D008745:Methylation / Q000187:drug effects; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D011802:Quinidine / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism*; D013237:Stereoisomerism; D013426:Sulfaphenazole / Q000494:pharmacology
D003577:Cytochrome P-450 Enzyme System; D005473:Fluoxetine; D007527:Isoenzymes; D007654:Ketoconazole; D011802:Quinidine; D011994:Recombinant Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D013426:Sulfaphenazole