Abstract
Background:
Fluoxetine, belonging to the class of selective serotonin uptake inhibitors, has been
extensively used for the treatment of depression and other psychiatry related disorders.
Fluoxetine (CAS 59333-67-4) is a substrate of polymorphic cytochrome P450 2D6 isozyme
(CYP2D6) leading to the formation of norfluoxetine (CAS 83891-03-06), which is not
only active but long lived than the parent in the systemic circulation. Since the
parent and metabolite levels are important from a therapeutic perspective, knowledge
of phenotypic distribution of the population may be an important consideration.
Objective:
The aim of the work was to retrospectively evaluate the pharmacokinetic data of fluoxetine
and norfluoxetine from several bioavailability/bioequivalence (BA/BE) studies to identify
the poor metabolizer (PM) phenotypes from the unsuspected healthy subjects across
varied protocol designs, dose sizes and differing formulations.
Methods:
The pharmacokinetic data of fluoxetine and norfluoxetine were gathered from several
BA/BE studies conducted at clinical facilities located at Bangalore and Chennai, India.
The BA/BE studies involved open label, two-way randomized crossover designs with two
periods and two treatments (reference and test). Blood samples were collected for
at least 672 h after fluoxetine dosing and the plasma was analyzed using validated
tandem liquid chromatography mass spectrometric assay to determine fluoxetine and
norfluoxetine levels. Standard pharmacokinetic parameters were computed using noncompartmental
methods. For the purpose of this paper, retrospective evaluation of pharmacokinetic
data from only the reference formulation was considered. The AUC ratio of fluoxetine/norfluoxetine
was computed. The individual fluoxetine/norfluoxetine AUC0−∞ ratios were plotted in increasing rank order and using outlier test (‘T’procedure
at 5% level of significance) the subjects were categorized as extensive metabolizer
(EM) and PM phenotypes. The unequivocal confirmation of PM phenotypes was obtained
by performing linear regression analysis of fluoxetine vs norfluoxetine AUC0–∞ values.
Results:
Each study was evaluated for the distribution of EM and PM phenotypes of fluoxetine.
There were 144 subjects evaluable from four studies, 89.6% (129 out of 144) of which
could be categorised as EMs and 10.4% (15 out of 144) as PMs of fluoxetine. The pharmacokinetic
parameters were quite distinct between the two phenotypes: (1) PM phenotypes showed
much higher exposure (approximately 2.3-fold increase in AUC0−∞) and much slower elimination (almost 2-fold increase in elimination half-life) for
fluoxetine as compared to EM phenotypes; (2) PM phenotypes showed approximately 0.5-fold
lower exposure of norfluoxetine as compared to the EM counter parts; (3) There was
no change (approximately 1.2-fold) in the elimination half life of norfluoxetine in
EM and PM phenotypes
Conclusions:
Retrospective evaluation of fluoxetine and norfluoxetine pharmacokinetic data demonstrated
existence of both PM and EM phenotypes in the Indian population. Based on the overall
data (n = 144 subjects) there appeared to be 10.4% of PM phenotypes for fluoxetine
and/or possibly for other polymorphic CYP2D6 substrates commonly used in this region.
Key words
Anti-depressant drugs - CAS59333-67-4 - CAS83891-03-6 - Fluoxetine - Norfluoxetine
- Polymorphic CP2D6 substrates
