Content uploaded by Mohammad Hailat
Author content
All content in this area was uploaded by Mohammad Hailat on Feb 22, 2024
Content may be subject to copyright.
Citation: Zakaraya, Z.; Abu Assab,
M.; Tamimi, L.N.; Karameh, N.; Hailat,
M.; Al-Omari, L.; Abu Dayyih, W.;
Alasasfeh, O.; Awad, M.; Awad, R.
Pharmacokinetics and
Pharmacodynamics: A
Comprehensive Analysis of the
Absorption, Distribution, Metabolism,
and Excretion of Psychiatric Drugs.
Pharmaceuticals 2024,17, 280. https://
doi.org/10.3390/ph17030280
Academic Editor: Abdeslam
Chagraoui
Received: 17 January 2024
Revised: 30 January 2024
Accepted: 10 February 2024
Published: 22 February 2024
Copyright: © 2024 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
pharmaceuticals
Review
Pharmacokinetics and Pharmacodynamics: A Comprehensive
Analysis of the Absorption, Distribution, Metabolism, and
Excretion of Psychiatric Drugs
Zainab Zakaraya 1, * , Mohammad Abu Assab 2, Lina N. Tamimi 2, Nida Karameh 1, Mohammad Hailat 3,
Laila Al-Omari 4, Wael Abu Dayyih 5, Omar Alasasfeh 5, Mohammad Awad 6and Riad Awad 6
1Faculty of Pharmacy, Al-Ahliyya Amman University, Amman 19111, Jordan; nidakarameh@ammanu.edu.jo
2Faculty of Pharmacy, Zarqa University, Zarqa 13132, Jordan; mabuassab@zuj.edu.jo (M.A.A.);
ltamimi@zuj.edu.jo (L.N.T.)
3Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman 11733, Jordan; m.hailat@zuj.edu.jo
4Faculty of Allied Medical Sciences, Al-Ahliyya Amman University, Amman 19111, Jordan;
l.omari@ammanu.edu.jo
5Faculty of Pharmacy, Mutah University, Al-Karak 61710, Jordan; wabudayyih@mutah.edu.jo (W.A.D.);
omarasasfeh90@mutah.edu.jo (O.A.)
6Faculty of Pharmacy and Medical Sciences, University of Petra, Amman 11196, Jordan;
mohammadrawad00@gmail.com (M.A.); rawad@uop.edu.jo (R.A.)
*Correspondence: z.zakaraya@ammanu.edu.jo
Abstract: The two main classifications of antidepressant medications are selective norepinephrine
reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs). Out of the available
choices, selective serotonin reuptake inhibitors (SSRIs) have emerged as the most commonly pre-
scribed option. The class demonstrates a greater degree of diversity in its structural characteristics in
contrast to its neurochemical effects. Nevertheless, it is important to acknowledge that the chemical
composition of a drug within this specific class does not carry substantial significance in the selection
process. A comprehensive analysis of the pharmacodynamic and pharmacodynamic properties of
antidepressant drugs proves advantageous for clinicians and managed care providers responsible for
selecting preferred selective serotonin reuptake inhibitors (SSRIs) from a roster of authorized medica-
tions. The physicochemical characteristics, which possess considerable significance, are frequently
disregarded except during the drug development stage. Pharmacodynamic properties refer to the
physiological and biochemical effects that drugs exert on the human body. It is noteworthy that the
inclusion of selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake
inhibitors (SNRIs) in a comprehensive depression management protocol may demonstrate enhanced
effectiveness in clinical environments as opposed to controlled trials.
Keywords: pharmacokinetics; pharmacodynamics; absorption; distribution; metabolism; excretion;
psychiatric drugs
1. Introduction
Psychiatric disorders are costly disorders worldwide. Their treatment and follow-
up need much more time, cost, and effort [
1
]. The rate of these disorders has increased
worldwide, with more consumption of their drugs and more exacerbated side effects. The
need for novel, innovative medicines with improved pharmacological properties and fewer
adverse events is mandatory [
2
,
3
]. The following Figure 1shows the rate of the use of
psychiatric drugs worldwide.
Pharmaceuticals 2024,17, 280. https://doi.org/10.3390/ph17030280 https://www.mdpi.com/journal/pharmaceuticals
Pharmaceuticals 2024,17, 280 2 of 16
Pharmaceuticals 2021, 14, x FOR PEER REVIEW 2 of 18
Figure 1. The rate of using psychiatric drugs worldwide (per 1000 persons) [4].
The following Figure 2 illustrates the inhibitory constants (Ki) that inhibit monoam-
ine uptake into rat brain tissue. Specifically, the focus is on the effects of imipramine, se-
lective serotonin reuptake inhibitors, and N-demethylated metabolites, where 5-HT is also
known as 5-hydroxytryptamine and NA stands for noradrenaline [4].
Figure 2. The inhibitory constants (Ki) associated with inhibiting monoamine uptake into rat brain
tissue. Specifically, the focus is on the effects of imipramine, selective serotonin reuptake inhibitors,
and N-demethylate [5].
Selective serotonin reuptake inhibitors (SSRIs) are the first class of intentionally de-
veloped therapeutic medications in the field of psychiatry. After its introduction in Great
Britain in 1983, fluvoxamine was followed by the widespread availability of fluoxetine,
paroxetine, citalopram, and sertraline. Based on empirical evidence derived from clinical
trials, it is widely acknowledged that selective serotonin reuptake inhibitors (SSRIs) are
regarded as a viable alternative to tricyclic antidepressants (TCAs). In several countries,
there has been a replacement of tricyclic antidepressants (TCAs) with alternative pharma-
cological treatments that are considered the initial choice for managing depression.
Figure 1. The rate of using psychiatric drugs worldwide (per 1000 persons) [4].
The following Figure 2illustrates the inhibitory constants (Ki) that inhibit monoamine
uptake into rat brain tissue. Specifically, the focus is on the effects of imipramine, selective
serotonin reuptake inhibitors, and N-demethylated metabolites, where 5-HT is also known
as 5-hydroxytryptamine and NA stands for noradrenaline [4].
Pharmaceuticals 2021, 14, x FOR PEER REVIEW 2 of 18
Figure 1. The rate of using psychiatric drugs worldwide (per 1000 persons) [4].
The following Figure 2 illustrates the inhibitory constants (Ki) that inhibit monoam-
ine uptake into rat brain tissue. Specifically, the focus is on the effects of imipramine, se-
lective serotonin reuptake inhibitors, and N-demethylated metabolites, where 5-HT is also
known as 5-hydroxytryptamine and NA stands for noradrenaline [4].
Figure 2. The inhibitory constants (Ki) associated with inhibiting monoamine uptake into rat brain
tissue. Specifically, the focus is on the effects of imipramine, selective serotonin reuptake inhibitors,
and N-demethylate [5].
Selective serotonin reuptake inhibitors (SSRIs) are the first class of intentionally de-
veloped therapeutic medications in the field of psychiatry. After its introduction in Great
Britain in 1983, fluvoxamine was followed by the widespread availability of fluoxetine,
paroxetine, citalopram, and sertraline. Based on empirical evidence derived from clinical
trials, it is widely acknowledged that selective serotonin reuptake inhibitors (SSRIs) are
regarded as a viable alternative to tricyclic antidepressants (TCAs). In several countries,
there has been a replacement of tricyclic antidepressants (TCAs) with alternative pharma-
cological treatments that are considered the initial choice for managing depression.
Figure 2. The inhibitory constants (Ki) associated with inhibiting monoamine uptake into rat brain
tissue. Specifically, the focus is on the effects of imipramine, selective serotonin reuptake inhibitors,
and N-demethylate [5].
Selective serotonin reuptake inhibitors (SSRIs) are the first class of intentionally de-
veloped therapeutic medications in the field of psychiatry. After its introduction in Great
Britain in 1983, fluvoxamine was followed by the widespread availability of fluoxetine,
paroxetine, citalopram, and sertraline. Based on empirical evidence derived from clinical
trials, it is widely acknowledged that selective serotonin reuptake inhibitors (SSRIs) are
regarded as a viable alternative to tricyclic antidepressants (TCAs). In several countries,
there has been a replacement of tricyclic antidepressants (TCAs) with alternative phar-
macological treatments that are considered the initial choice for managing depression.
Regarding their therapeutic efficacy, both selective serotonin reuptake inhibitors (SSRIs)
and tricyclic antidepressants (TCAs) demonstrate comparable levels of potency. Selective
serotonin reuptake inhibitors (SSRIs) demonstrate a noteworthy lack of potentially fatal
adverse effects, such as harm to the heart and central nervous system (CNS), primar-
ily due to their restricted receptor antagonism. Selective serotonin reuptake inhibitors
(SSRIs) are widely regarded as safe and easily manageable in terms of their utilization and
Pharmaceuticals 2024,17, 280 3 of 16
administration. Based on a survey conducted in Sweden, encompassing a sample size
of 1202 reports documenting adverse reactions to selective serotonin reuptake inhibitors
(SSRIs), the predominant occurrences reported were associated with neurological symp-
toms (22.4%), psychiatric symptoms (19.4%), and gastrointestinal symptoms (18%) [
5
].
The potential exists for a shift in the treatment approach for depression with antidepres-
sant medications from predominantly inpatient settings to outpatient settings due to the
favorable safety profile demonstrated by selective serotonin reuptake inhibitors (SSRIs).
Moreover, the application of selective serotonin reuptake inhibitors (SSRIs) has been
extended beyond the management of major depression to encompass minor depression and
other psychiatric disorders that have been postulated to be associated with a compromised
serotonin system. The conditions above include anxiety disorders, obsessive–compulsive
disorders, and premenstrual dysphoric disorders. Hence, the use of selective serotonin reuptake
inhibitors (SSRIs) may be regarded as a rational and mechanism-based therapeutic strategy [
6
].
These abnormalities include non-linear kinetics, discrepancies between genders, varia-
tions related to age, and relevant drug–drug interactions that have clinical implications.
The class of antidepressant medications known as serotonin–norepinephrine reuptake
inhibitors (SNRIs) operates by impeding the reuptake of serotonin and norepinephrine neu-
rotransmitters. These medications are frequently categorized as a group of interconnected
antidepressants that function by inhibiting the process of reuptake [
7
]. Nevertheless, these
substances commonly display discernible variations in their chemical compositions and
pharmacological properties [8].
Serotonin–norepinephrine reuptake inhibitors (SNRIs) are a pharmacological class of
antidepressant medications that exert their therapeutic effects by impeding the reuptake
process of both serotonin and norepinephrine neurotransmitters. This article investigates
the differences among serotonin–norepinephrine reuptake inhibitors (SNRIs), including
factors such as the year of approval by the United States Food and Drug Administration,
availability of generic versions, approved clinical indications, duration of action, metabolic
processes and elimination, presence or absence of active metabolites, recommended dosing
regimens, relative effects on serotonin and norepinephrine, and the temporal pattern of
serotonin and norepinephrine reuptake (sequential or simultaneous). It is important to
reiterate that serotonin–norepinephrine reuptake inhibitors (SNRIs) are classified as a type
of antidepressant medication. Nevertheless, it is crucial to acknowledge that SNRIs exhibit
a significant array of variations, which may have potential implications for the clinical
treatment of patients.
The following Figure 3shows a comparison between SNRI and SSRI adherence in the
years 2015, 2020, and 2023 [2].
Pharmaceuticals 2021, 14, x FOR PEER REVIEW 4 of 18
Figure 3. The adherence to SSRIs and SNRIs in three different years [2].
2. Selective Serotonin Reuptake Inhibitors
2.1. Pharmacodynamics
2.1.1. Fluoxetine
Fluoxetine was the first selective serotonin reuptake inhibitor (SSRI) to be widely in-
troduced for clinical use in most countries. The compound being discussed is a racemic
mixture comprising two enantiomers. It is essential to acknowledge that the S-enantiomer
demonstrates a greater potency, by approximately 1.5 times, in inhibiting serotonin
reuptake than the R-enantiomer [7].
The pharmacological differentiation between enantiomers is notably apparent in the
context of the active metabolite norfluoxetine, wherein the S-enantiomer demonstrates
approximately 20-fold higher efficacy in inhibiting reuptake than the R-enantiomer. In a
state of equilibrium [9], it is commonly observed that the concentration of racemic
norfluoxetine exceeds that of racemic fluoxetine. The levels of the N-demethylated metab-
olite are relatively higher in blood samples of S-norfluoxetine compared with R-norfluox-
etine [10]. Regarding protein binding, fluoxetine exhibits a notable degree of lipophilicity
and demonstrates a high affinity for plasma proteins, facilitating its distribution to the
central nervous system with its active metabolite, norfluoxetine. The variability in the vol-
ume of distribution of fluoxetine and its metabolite ranges from 20 to 42 L/kg. The plasma
protein binding of fluoxetine is estimated to be around 94% [7,11,12].
2.1.2. Paroxetine
Paroxetine is widely regarded as the most effective serotonin reuptake inhibitor cur-
rently available for clinical application. Nevertheless, it demonstrates a relatively dimin-
ished degree of selectivity toward the serotonin reuptake site compared with fluvoxamine
or sertraline. Moreover, it has been noted that it shows a similar degree of blockade of
muscarinic acetylcholine receptors as the tricyclic antidepressants (TCAs) imipramine or
doxepin. It exhibits even higher effectiveness in this aspect when compared with desipra-
mine or maprotiline. Notwithstanding this aribute, the manifestation of anticholinergic
adverse effects is anticipated to be confined to toxic concentrations of paroxetine, which
surpass the dosages required for therapeutic efficacy [13].
Regarding protein binding, paroxetine exhibits a high degree of plasma protein bind-
ing, with around 95% of the drug being bound [14]. Paroxetine metabolism occurs mainly
in the liver and is predominantly facilitated by the cytochrome enzyme CYP2D6, with
0
2
4
6
8
10
12
14
16
2015 2020 2023
0.8
2.5
9.1
7.5
13.1
14.2
SNRIs SSRIs
Figure 3. The adherence to SSRIs and SNRIs in three different years [2].
Pharmaceuticals 2024,17, 280 4 of 16
2. Selective Serotonin Reuptake Inhibitors
2.1. Pharmacodynamics
2.1.1. Fluoxetine
Fluoxetine was the first selective serotonin reuptake inhibitor (SSRI) to be widely
introduced for clinical use in most countries. The compound being discussed is a racemic
mixture comprising two enantiomers. It is essential to acknowledge that the S-enantiomer
demonstrates a greater potency, by approximately 1.5 times, in inhibiting serotonin reuptake
than the R-enantiomer [7].
The pharmacological differentiation between enantiomers is notably apparent in the
context of the active metabolite norfluoxetine, wherein the S-enantiomer demonstrates
approximately 20-fold higher efficacy in inhibiting reuptake than the R-enantiomer. In a
state of equilibrium [
9
], it is commonly observed that the concentration of racemic norflu-
oxetine exceeds that of racemic fluoxetine. The levels of the N-demethylated metabolite are
relatively higher in blood samples of S-norfluoxetine compared with R-norfluoxetine [10].
Regarding protein binding, fluoxetine exhibits a notable degree of lipophilicity and demon-
strates a high affinity for plasma proteins, facilitating its distribution to the central nervous
system with its active metabolite, norfluoxetine. The variability in the volume of distribu-
tion of fluoxetine and its metabolite ranges from 20 to 42 L/kg. The plasma protein binding
of fluoxetine is estimated to be around 94% [7,11,12].
2.1.2. Paroxetine
Paroxetine is widely regarded as the most effective serotonin reuptake inhibitor cur-
rently available for clinical application. Nevertheless, it demonstrates a relatively dimin-
ished degree of selectivity toward the serotonin reuptake site compared with fluvoxamine
or sertraline. Moreover, it has been noted that it shows a similar degree of blockade of
muscarinic acetylcholine receptors as the tricyclic antidepressants (TCAs) imipramine
or doxepin. It exhibits even higher effectiveness in this aspect when compared with
desipramine or maprotiline. Notwithstanding this attribute, the manifestation of anticholin-
ergic adverse effects is anticipated to be confined to toxic concentrations of paroxetine,
which surpass the dosages required for therapeutic efficacy [13].
Regarding protein binding, paroxetine exhibits a high degree of plasma protein
binding, with around 95% of the drug being bound [
14
]. Paroxetine metabolism oc-
curs mainly in the liver and is predominantly facilitated by the cytochrome enzyme
CYP2D6, with additional involvement from CYP3A4 and potentially other cytochrome en-
zymes. The pharmacokinetics of this medicine may be affected by genetic variations in the
CYP2D6 enzyme [15–17].
2.2. Pharmacokinetics
2.2.1. Absorption
Fluoxetine
Fluoxetine is absorbed extensively after oral administration. Hepatic first-pass metabolism
leads to a decrease in oral bioavailability to below 90%. Similar to other lipophilic drugs,
fluoxetine has a significant volume of distribution (V
d
) ranging from 14 to 100 L/kg, indicating
substantial accumulation in tissues. Fluoxetine exhibits the highest volume of distribution (V
d
)
when compared with other selective serotonin reuptake inhibitors (SSRIs) [
18
,
19
]. The chemical
is most highly concentrated in the lungs due to its significant abundance of lysosomes. A
commonly held hypothesis suggests that the occurrence of lysosomal entrapment influences the
increase in the volume of distribution (V
d
) associated with fluoxetine. Although the volume of
distribution (V
d
) is larger, similar to tricyclic antidepressants (TCAs), the accumulation of this
selective serotonin reuptake inhibitor (SSRI) in the brain is significantly lower compared with
other SSRIs [
20
]. This phenomenon has been confirmed through laboratory experiments using
brain tissue samples and real-time observations made on patients using fluorine-19 nuclear
magnetic resonance spectroscopy (NMRS). The ratio of fluoxetine concentration in the brain to
Pharmaceuticals 2024,17, 280 5 of 16
the concentration in the rest of the body is 2.6:1 in patients, whereas for fluvoxamine, the ratio
is 24:1 [21].
Paroxetine
Paroxetine is an example of a selective serotonin reuptake inhibitor (SSRI) that demon-
strates chirality and is commercially accessible as a solitary enantiomer [
22
]. The observed
phenomenon leads to a higher level of consistency in pharmacokinetics when comparing
enantiopure selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine or citalopram,
with racemic SSRIs. Paroxetine exhibits effective absorption from the gastrointestinal tract,
albeit experiencing rapid metabolism during its initial passage through the liver [
23
]. A
considerable portion of paroxetine, estimated to be around 36%, undergoes elimination via
fecal excretion. However, less than 1% of this quantity is excreted in its unchanged state.
The observed range of the volume of distribution (V
d
), which spans from 2 to 12 L/kg,
demonstrates a resemblance to that of fluvoxamine [
24
]. The duration and dosage of ad-
ministration contribute to the variability in the elimination half-life (t
1/2
). After 15 days of
oral administration at a dosage of 20 mg per day, the substance exhibits an increase in its
half-life (t1/2) by approximately 12%, leading to a range of 16.4 to 18.3 h. Furthermore, upon
increasing the oral dosage to 30 mg of paroxetine per day, there is an observed increase in
the half-life by more than 100%, falling within a range of 9.8 to 21.0 h. The manifestation of
temporal effects becomes increasingly apparent when contrasting the integral of the curve
(AUC) after a solitary administration with that after multiple administrations [
25
]. Even
when administered at a lower dosage of 20 mg per day, a notable elevation in the area under
the concentration–time curve (AUC) was observed, with values rising from 191 ng/hr/mL
to 1481 ng/hr/mL [
25
,
26
]. Based on the existing body of literature, it has been observed
that the bioavailability of the substance is less than 50% when administered as a single
dose. However, there is a notable increase in bioavailability when multiple doses are ad-
ministered [
27
]. Paroxetine is efficiently absorbed through the gastrointestinal system and
undergoes a first metabolism in the liver. The primary drug undergoes conversion into
metabolites that lack pharmacological activity. Cytochrome P450 2D6 (CYP2D6) is the primary
enzyme that converts paroxetine into the paroxetine catechol intermediate. The elimination of
paroxetine is characterized by a high-affinity saturable process closely associated with CYP2D6
activity and an extra low-affinity linear process [
15
,
28
].
In vitro
tests suggest that CYP1A2,
CYP3A4/5, and CYP2C19 have a limited role in the production of paroxetine catechol, where
the results categorize the level of participation in the formation as follows: CYP2D6 has
the highest rank, followed by CYP3A4, CYP1A2, CYP2C19, and CYP3A5. A simulation
conducted on a population determined that CYP3A4 and CYP1A2 are the most probable
enzymes involved in the metabolism of paroxetine in persons with decreased CYP2D6 activity,
specifically those who are classified as CYP2D6 poor metabolizers (PMs) [
29
,
30
]. Paroxetine
catechol is excreted in the form of conjugates of subsequent metabolites M-I (BRL 36610;
(3S,4R)-4-(4-fluorophenyl)-3-(4-hydroxy-3-methoxyphenoxymethyl)piperidine), M-II (BRL
36583; (3S,4R)-4-(4-fluorophenyl)-3-(3-hydroxy-4-methoxyphenoxymethyl)piperidine), M-III
(BRL 35961; (3S,4R)-4-(4-fluorophenyl)-3-(hydroxymethyl)piperidine), and other metabolites
that are soluble in water. Catechol-O-methyltransferase (COMT) methylates it, resulting
in the formation of metabolites M-I and M-II (Figure 1) [Articles: 10755376, 1531950]. We
know that the enzymes responsible for forming glucuronide and sulfate conjugates have not
been documented [19,31].
Paroxetine is a potent inhibitor of the enzyme CYP2D6, which can affect its breakdown
in the body and mimic the genetic characteristics of individuals who metabolize drugs
in a certain way. This can also impact the metabolism of other medications dependent
on CYP2D6. Research indicates that metoprolol, clozapine, desipramine, imipramine,
and a combination of dextromethorphan and quinidine can affect plasma concentrations
and metabolism [16].
Pharmaceuticals 2024,17, 280 6 of 16
2.2.2. Distribution
Fluoxetine
Fluoxetine demonstrates an extended half-life (t
1/2
) that spans a duration of 1 to 4 days.
The variability in the half-life of norfluoxetine is observed with a range that encompasses a
duration of 7 to 15 days [
31
]. Steady-state conditions require a substantial period ranging
from 1 to 22 months, primarily due to the prolonged half-life. The pharmacokinetics of
fluoxetine exhibit non-linear characteristics, as indicated by an amplified increase in its
plasma levels following an escalation in dosage [
32
]. Upon administration of multiple
doses, it has been observed that there is an increase in the half-life (t
1/2
) and a decrease in
oral clearance compared with the administration of single doses. In the context of rats, it has
been observed that the bioavailability of fluoxetine exhibits an upward trend as the dosage
is escalated. This observation implies the existence of a saturable first-pass metabolism
mechanism for fluoxetine in rats. Insufficient evidence exists regarding aberrations in the
excretion kinetics of fluoxetine in individuals with renal dysfunction. Nevertheless, there is
evidence to suggest that liver cirrhosis has a substantial impact on the plasma clearance
of fluoxetine [32].
Paroxetine
The distribution as pharmacokinetics of paroxetine demonstrates nonlinearity, which
can be delineated by two distinct mechanisms: a low-capacity, high-affinity process and
a high-capacity, low-affinity process that adheres to a linear pattern. Nevertheless, this
assertion is only relevant to individuals categorized as extensive metabolizers (EMs) of
CYP2D6 [
31
]. Elderly individuals commonly demonstrate extended plasma concentrations
at steady-state and the elimination half-life. Renal impairment has minimal impact on the
pharmacokinetics of paroxetine, whereas hepatic dysfunction may lead to a reduction in
paroxetine clearance [33].
2.2.3. Metabolism
Fluoxetine
Fluoxetine undergoes significant metabolic conversion, leading to the generation of
the active metabolite norfluoxetine alongside several other metabolites [
34
]. After being
administered orally, the primary way fluoxetine is eliminated from the body is through
excretion in the urine. A small fraction, comprising less than 10% of the total, is elim-
inated from the body either unchanged or as fluoxetine N-glucuronide. Thus far, a re-
stricted quantity of investigations has been undertaken to scrutinize the precise CYP isoen-
zymes accountable for the metabolic pathways of fluoxetine. Nevertheless, the results
obtained from these studies have failed to yield conclusive findings [
32
]. The central fo-
cus of the investigation has primarily centered on the mechanism of N-demethylation of
fluoxetine [
33
,
35
]. According to a prior study, there was notable participation of the en-
zyme CYP2D6 in the N-demethylation process of fluoxetine among both healthy individuals
and psychiatric patients who underwent a medication transition from fluoxetine to paroxe-
tine [
36
]. On the other hand, the pharmacokinetics of fluoxetine and norfluoxetine are not
influenced by paroxetine, a potent inhibitor of CYP2D6. There is a dearth of information about
the precise enzymes that account for more than 70% of the biotransformation mechanism
of fluoxetine [34,37].
Fluoxetine undergoes significant hepatic metabolism. The sole active metabolite found
in norfluoxetine is produced through the demethylation of fluoxetine. Fluoxetine consists of
a racemic blend of two enantiomers. S-fluoxetine has a somewhat more remarkable ability
to block serotonin reabsorption than R-fluoxetine. The disparity is far more evident for
the active metabolite. The reuptake-inhibiting potency of S-norfluoxetine is approximately
20 times greater than that of R-norfluoxetine. Additionally, these four chemicals also exhibit
variations in their kinetics. After several weeks of treatment, the plasma concentration of
both S-enantiomers is approximately twice as high as that of the R-enantiomers [10,33].
Pharmaceuticals 2024,17, 280 7 of 16
The principal elimination pathway mainly involves oxidative metabolism and conju-
gation. However, the identity of over half of the resulting metabolic byproducts remains
unidentified. The primary route of elimination for fluoxetine is urinary excretion, with
less than 10% being eliminated in its original form or as fluoxetine glucuronide. Multiple
in vitro
and
in vivo
investigations provide evidence suggesting that CYP2D6, CYP2C19,
CYP2C9, CYP3A4, and CYP3A5 are involved, to some extent, in the conversion of R- and
S-fluoxetine into its N-desmethyl metabolites [
35
]. The cytochrome P450 isoforms display
genetic variations that impact their ability to catalyze reactions. Studies on patients with
various CYP2D6 and CYP2C9 genotypes revealed that CYP2C9 primarily facilitates the
process of R-fluoxetine demethylation, while S-norfluoxetine production relies heavily on
CYP2D6. Simultaneously, the enantiomers of fluoxetine and norfluoxetine inhibit CYP2D6-
mediated processes. Hence, the significance of CYP2C19, CYP2C9, CYP3A4, and CYP3A5
in the metabolism of fluoxetine becomes more prominent after long-term administration
since the involvement of CYP2D6 is reduced due to the inhibitory effects of fluoxetine
and norfluoxetine [36].
Furthermore, fluoxetine has shown inhibitory efficacy against CYP2C19, CYP2C9, and
CYP3A4 in laboratory investigations. Each of these CYP isoenzymes has a role in the break-
down of many medicines. As a result, fluoxetine and norfluoxetine can potentially affect
the breakdown and movement of pharmaceuticals taken together. The inhibitory effect of
fluoxetine and norfluoxetine on the isoenzyme CYP2D6 has been found to cause clinically
significant medication interactions with tricyclic antidepressants and neuroleptics [34].
According to the results obtained from an
in vitro
investigation, it was observed
that the enzyme CYP2C9 plays a substantial role in the process of N-demethylation of
fluoxetine. Furthermore, it is worth noting that the process under consideration may
involve the participation of the CYP2C19 and a CYP3A isoform [
38
]. Nevertheless, it was
found that the contribution of CYP2D6 was deemed to be inconsequential. Recent research
has revealed a noteworthy association between the enzymatic activity of CYP2D6 and the
elimination rate of R- and S-fluoxetine, along with S-norfluoxetine. Nevertheless, a lack of
correlation was found for R-norfluoxetine [39].
The following Figure 4shows the metabolism of fluoxetine [8].
Pharmaceuticals 2021, 14, x FOR PEER REVIEW 8 of 18
elimination rate of R- and S-fluoxetine, along with S-norfluoxetine. Nevertheless, a lack of
correlation was found for R-norfluoxetine [39].
The following Figure 4 shows the metabolism of fluoxetine [8].
Figure 4. The in vivo metabolism of fluoxetine [8].
Paroxetine
Similar to other lipophilic psychotropic drugs, paroxetine undergoes extensive he-
patic metabolism to generate more hydrophilic metabolites that can be eliminated from
the body [14]. Metabolism involves the enzymatic breakdown of the methylenedioxy
bridge through oxidation, producing a labile catechol intermediate. The intermediate un-
dergoes subsequent methylation, forming either the meta-methoxy derivative when meth-
ylated in the meta-position or the para-methoxy derivative when methylated in the para-
position. Both metabolites undergo further conjugation with either sulfuric acid or glucu-
ronic acid [40]. There is no presumption regarding the potential contribution of any me-
tabolites to the pharmacological effects of paroxetine [41].
The facilitation of the oxidative cleavage process is likely aributed to the presence
of CYP isoenzymes, while additional enzymes are necessary for methylations. The enzy-
matic activity responsible for the O-methylation process is believed to be facilitated by
catechol-O-methyltransferase, an enzyme involved in deactivating catecholamines and
catechol estrogens. It is essential to highlight that the urine of individuals classified as
poor metabolizers (PMs) exhibited notably reduced levels of the meta-O-methyl metabo-
lite or its glucuronide and sulfate conjugates [40]. Nevertheless, the quantities of the glu-
curonic acid conjugate of the para-O-methyl metabolite were discovered to be comparable
in both extensive metabolizers (EMs) and poor metabolizers (PMs). However, it has been
observed that PMs exhibit the capacity to produce the meta-O-methyl metabolite [42]. The
differences observed between EMs and PMs are more likely to be aributed to variations
in their respective abilities to make the catechol intermediate rather than differences in
their methylation activities [43,44] As illustrated in Figure 5 [44].
Figure 4. The in vivo metabolism of fluoxetine [8].
Paroxetine
Similar to other lipophilic psychotropic drugs, paroxetine undergoes extensive hep-
atic metabolism to generate more hydrophilic metabolites that can be eliminated from
the body [
14
]. Metabolism involves the enzymatic breakdown of the methylenedioxy
bridge through oxidation, producing a labile catechol intermediate. The intermediate
undergoes subsequent methylation, forming either the meta-methoxy derivative when
methylated in the meta-position or the para-methoxy derivative when methylated in the
para-position. Both metabolites undergo further conjugation with either sulfuric acid or
Pharmaceuticals 2024,17, 280 8 of 16
glucuronic acid [
40
]. There is no presumption regarding the potential contribution of any
metabolites to the pharmacological effects of paroxetine [41].
The facilitation of the oxidative cleavage process is likely attributed to the presence
of CYP isoenzymes, while additional enzymes are necessary for methylations. The enzy-
matic activity responsible for the O-methylation process is believed to be facilitated by
catechol-O-methyltransferase, an enzyme involved in deactivating catecholamines and
catechol estrogens. It is essential to highlight that the urine of individuals classified as poor
metabolizers (PMs) exhibited notably reduced levels of the meta-O-methyl metabolite or
its glucuronide and sulfate conjugates [
40
]. Nevertheless, the quantities of the glucuronic
acid conjugate of the para-O-methyl metabolite were discovered to be comparable in both
extensive metabolizers (EMs) and poor metabolizers (PMs). However, it has been observed
that PMs exhibit the capacity to produce the meta-O-methyl metabolite [
42
]. The differ-
ences observed between EMs and PMs are more likely to be attributed to variations in
their respective abilities to make the catechol intermediate rather than differences in their
methylation activities [43,44] As illustrated in Figure 5[44].
Pharmaceuticals 2021, 14, x FOR PEER REVIEW 9 of 18
Figure 5. The in vivo metabolism of paroxetine [44].
2.2.4. Excretion
Fluoxetine
This drug exhibits renal excretion of approximately 2.5% in its unchanged form,
while about 10% is excreted as norfluoxetine.
Paroxetine
During a 10-day post-dosing period, it was observed that approximately 64% of a 30
mg oral solution dose of paroxetine was eliminated through urinary excretion. Of this
amount, 2% was identified as the parent compound, while 62% was identified as metabo-
lites [44].
The following Figure 6 summarizes the dose–response curve comparing paroxetine
and fluoxetine.
Figure 5. The in vivo metabolism of paroxetine [44].
2.2.4. Excretion
Fluoxetine
This drug exhibits renal excretion of approximately 2.5% in its unchanged form, while
about 10% is excreted as norfluoxetine.
Paroxetine
During a 10-day post-dosing period, it was observed that approximately 64% of a
30 mg oral solution dose of paroxetine was eliminated through urinary excretion. Of
this amount, 2% was identified as the parent compound, while 62% was identified as
metabolites [44].
The following Figure 6summarizes the dose–response curve comparing paroxetine
and fluoxetine.
Pharmaceuticals 2024,17, 280 9 of 16
Pharmaceuticals 2021, 14, x FOR PEER REVIEW 10 of 18
Figure 6. The dose–response curve that compares fluoxetine (FLX) and paroxetine (PAE) [45].
3. Drug–drug interactions between SSRIs, SNRIs, and other drugs
Paroxetine has been recognized as the most efficacious inhibitor of the cytochrome
P450 2D6 enzyme (CYP2D6) among all selective serotonin reuptake inhibitors (SSRIs). The
average inhibition constant (Ki) value for inhibiting the CYP2D6 enzyme is typically ob-
served to be in the nanomolar range, specifically around 150 nM. This is analogous to the
efficacy of quinidine (Ki = 30 nM), which is presently acknowledged as the most potent
antagonist of CYP2D6 [45].
Most studies or case reports that have examined inhibitory potency have focused on
evaluating the inhibition of metabolism in tricyclic antidepressants (TCAs), particularly
imipramine, desipramine, or trimipramine. The potency of inhibiting N-demethylated
metabolites of tricyclic antidepressants (TCAs), such as desipramine, is considerably more
significant when compared with tertiary amines [46]. This observation is consistent with
the finding that CYP2D6 plays a substantial role in eliminating secondary amines, but its
importance is reduced in the metabolic elimination of tertiary amines. The extent of
CYP2D6 inhibition is correlated with the concentrations of paroxetine in the circulatory
system [47]. This may offer a potential rationale for the disparate findings observed in two
studies investigating the effects of paroxetine on the pharmacokinetics of clozapine, an
atypical antipsychotic medication. The administration of dosages surpassing 20 mg per
day, with an average of 31 mg per day, led to a notable increase in clozapine plasma con-
cen trat ions. In con trast , a stead y dail y dosage of 20 mg of parox etine does not si gnificantly
alter clozapine concentrations [10].
Studies conducted on sertraline have indicated limited clinical implications about
pharmacokinetic interactions with other medications. Nevertheless, it is essential to
acknowledge that the concurrent use of sertraline and warfarin has been linked to a sub-
stantial 8.9% elevation in prothrombin time, a factor that could potentially have significant
consequences [48]. Hiemke and Härer (2000) conducted a study to investigate the poten-
tial inhibitory effects of sertraline and its N-demethylated metabolite, 20 C, on the enzyme
CYP2D6. This investigation was carried out using in vitro experiments [11]. The results
indicated a notable level of inhibitory effectiveness, as evidenced by a Ki value of 0.7 mM.
However, patient research has not yielded any substantial clinical significance. There was
no significant inhibitory effect observed for sertraline, even when it was administered at
Figure 6. The dose–response curve that compares fluoxetine (FLX) and paroxetine (PAE) [45].
3. Drug–Drug Interactions between SSRIs, SNRIs, and Other Drugs
Paroxetine has been recognized as the most efficacious inhibitor of the cytochrome
P450 2D6 enzyme (CYP2D6) among all selective serotonin reuptake inhibitors (SSRIs).
The average inhibition constant (Ki) value for inhibiting the CYP2D6 enzyme is typically
observed to be in the nanomolar range, specifically around 150 nM. This is analogous to
the efficacy of quinidine (Ki = 30 nM), which is presently acknowledged as the most potent
antagonist of CYP2D6 [45].
Most studies or case reports that have examined inhibitory potency have focused on
evaluating the inhibition of metabolism in tricyclic antidepressants (TCAs), particularly
imipramine, desipramine, or trimipramine. The potency of inhibiting N-demethylated
metabolites of tricyclic antidepressants (TCAs), such as desipramine, is considerably more
significant when compared with tertiary amines [
46
]. This observation is consistent with
the finding that CYP2D6 plays a substantial role in eliminating secondary amines, but its
importance is reduced in the metabolic elimination of tertiary amines. The extent of CYP2D6
inhibition is correlated with the concentrations of paroxetine in the circulatory system [
47
].
This may offer a potential rationale for the disparate findings observed in two studies
investigating the effects of paroxetine on the pharmacokinetics of clozapine, an atypical
antipsychotic medication. The administration of dosages surpassing 20 mg per day, with
an average of 31 mg per day, led to a notable increase in clozapine plasma concentrations.
In contrast, a steady daily dosage of 20 mg of paroxetine does not significantly alter
clozapine concentrations [10].
Studies conducted on sertraline have indicated limited clinical implications about
pharmacokinetic interactions with other medications. Nevertheless, it is essential to ac-
knowledge that the concurrent use of sertraline and warfarin has been linked to a substantial
8.9% elevation in prothrombin time, a factor that could potentially have significant con-
sequences [
48
]. Hiemke and Härtter (2000) conducted a study to investigate the potential
inhibitory effects of sertraline and its N-demethylated metabolite, 20 C, on the enzyme
CYP2D6. This investigation was carried out using
in vitro
experiments [
11
]. The results
indicated a notable level of inhibitory effectiveness, as evidenced by a Ki value of 0.7 mM.
However, patient research has not yielded any substantial clinical significance. There was
no significant inhibitory effect observed for sertraline, even when it was administered at
high chronic doses alongside desipramine. Individuals with elevated levels of CYP2D6
activity at baseline demonstrated a moderate inhibitory characteristic [10].
Sertraline has been recognized as a substrate of the cytochrome P450 3A4 (CYP3A4)
enzyme, suggesting the potential for drug interactions involving this specific isoenzyme.
There is no documented evidence of any observed influence on the pharmacokinetics of
Pharmaceuticals 2024,17, 280 10 of 16
carbamazepine or midazolam, both of which are substrates of the enzyme CYP3A4, based
on
in vitro
studies. A restricted yet significant body of evidence derived from two recent
case reports suggests substantial hindrance in the metabolic process of clozapine due to the
administration of sertraline [38].
The serum concentration of clozapine, administered at a dosage of 600 mg, and
sertraline, administered at a dosage of 300 mg, was determined to be 1300 ng/mL. After
the cessation of sertraline, there was a reduction of 40% in the serum concentration of
clozapine [
49
]. Furthermore, it was observed that the administration of 50 mg of sertraline
resulted in a 2.1-fold increase in the concentration of clozapine in the bloodstream of a
patient who had been given 175 mg of clozapine. The observed augmentation in cognitive
focus ceased after selective serotonin reuptake inhibitor (SSRI) cessation. The case reports
above offer substantiating evidence for inhibiting CYP3A4 in vivo.
The potential role of CYP2C19 and CYP2D6 in the metabolism of citalopram implies
that changes in the functioning of these particular enzymes may have consequences. Af-
ter an extended period of citalopram administration, there is a slight reduction in the
activity of CYP2D6, which can be attributed to the inhibitory properties of N-desmethyl
citalopram [
50
]. There is a dearth of evidence suggesting any significant influence of
citalopram on the pharmacokinetics of CYP2C19 substrates. On the other hand, when
phenothiazine neuroleptics, specifically levomepromazine, are administered concurrently,
there is a notable 30% rise in the steady-state trough concentrations of citalopram. However,
this increase does not yield significant clinical consequences [50].
Levomepromazine, a well-established inhibitor of the enzyme CYP2D6, demonstrated
a significant impact by substantially increasing the steady-state concentrations of desmethyl
citalopram [
51
]. The prolonged administration of cimetidine at high doses (800 mg/day) led to
a significant decrease of 29% in the oral clearance of citalopram. This decrease was accompanied
by a corresponding increase of 43% in the blood concentration of citalopram [52].
The following Table 1shows the potential inhibitory and stimulatory effects of psychi-
atric drugs.
Table 1. The potential inhibitory and stimulatory effects of psychiatric drugs [11,14,21,24].
SSRI (Trade name) 1A2 2C9/10 2C19 2D6 3A3/4
Citalopram (Celexa) − − − ++ −
Escitalopram (Lexapro) − − − ++ −
Fluoxetine (Prozac) −++ ++ +++ +
Fluvoxamine (Luvox) +++ +++ +++ −++
Sertraline (Zoloft) − − − −
Paroxetine (Paxil) − − − − −
SNRIs 1A2 2C9/10 2C19 2D6 3A3/4
Duloxetine (Cymbalta) − − − ++ −
Venlafaxine (Effexor ER) − − − − −
Newer Antidepressants 1A2 2C9/10 2C19 2D6 3A3/4
Bupropion (Wellbutrin) ?? ?? ?? +++ ??
Nefazodone (Serzone) − − − − +++
?? = unknown; + = mild effect (20–50%); ++ = moderate effect (50–150%); +++ = substantial effect (>150);
−
= no
or minimal effect (<20).
4. Selective Norepinephrine Reuptake Inhibitor: Duloxetine
4.1. Pharmacodynamics
Duloxetine
Duloxetine, commercially known as Cymbalta™, obtained regulatory approval from
the Food and Drug Administration (FDA) in 2004 [
53
], thereby becoming the second selec-
Pharmaceuticals 2024,17, 280 11 of 16
tive serotonin–norepinephrine reuptake inhibitor (SNRI) to be sanctioned for utilization
within the United States [
19
]. The therapeutic effects of serotonin–norepinephrine reuptake
inhibitors (SNRIs) in the management of depression are attributed to their ability to initially
impede the activity of presynaptic transporter proteins responsible for the reabsorption
of serotonin and norepinephrine [
54
]. This process inhibits the reuptake of these neuro-
transmitters, causing changes in various homeostatic mechanisms, ultimately leading to
increased activation of postsynaptic receptors. However, there is variability in the binding
affinity of serotonin–norepinephrine reuptake inhibitors (SNRIs) toward the serotonin and
norepinephrine transporter. Desvenlafaxine, duloxetine, and venlafaxine demonstrate
higher efficacy in the inhibition of serotonin reuptake relative to norepinephrine reup-
take. In contrast, levomilnacipran and milnacipran exhibit a predilection for inhibiting
norepinephrine reuptake [35].
The following Figure 7compares the inhibitory effects of both duloxetine and fluoxe-
tine [16].
Pharmaceuticals 2021, 14, x FOR PEER REVIEW 12 of 18
− ++ − − − Duloxetine
(Cymbalta)
− − − − − Venlafaxine
(Effexor ER)
3A3/4 2D6 2C19 2C9/10 1A2 Newer Antide-
pressants
?? +++ ?? ?? ?? Bupropion
(Wellbutrin)
+++ − − − − Nefazodone
(Serzone)
? = unknown; + = mild effect (20–50%); ++ =moderate effect (50–150%); +++ = substantial effect (>150);
− = no or minimal effect (<20).
4. Selective Norepinephrine Reuptake Inhibitor: Duloxetine
4.1. Pharmacodynamics
Duloxetine
Duloxetine, commercially known as Cymbalta™, obtained regulatory approval from
the Food and Drug Administration (FDA) in 2004 [53], thereby becoming the second se-
lective serotonin–norepinephrine reuptake inhibitor (SNRI) to be sanctioned for utiliza-
tion within the United States [19]. The therapeutic effects of serotonin–norepinephrine
reuptake inhibitors (SNRIs) in the management of depression are aributed to their ability
to initially impede the activity of presynaptic transporter proteins responsible for the re-
absorption of serotonin and norepinephrine [54]. This process inhibits the reuptake of
these neurotransmiers, causing changes in various homeostatic mechanisms, ultimately
leading to increased activation of postsynaptic receptors. However, there is variability in
the binding affinity of serotonin–norepinephrine reuptake inhibitors (SNRIs) toward the
serotonin and norepinephrine transporter. Desvenlafaxine, duloxetine, and venlafaxine
demonstrate higher efficacy in the inhibition of serotonin reuptake relative to norepineph-
rine reuptake. In contrast, levomilnacipran and milnacipran exhibit a predilection for in-
hibiting norepinephrine reuptake [35].
The following Figure 7 compares the inhibitory effects of both duloxetine and fluox-
etine [16].
Figure 7. Inhibitory effects as a comparison between fluoxetine and duloxetine regarding pharma-
cokinetics [16].
Figure 7. Inhibitory effects as a comparison between fluoxetine and duloxetine regarding pharma-
cokinetics [16].
Serotonin–norepinephrine reuptake inhibitors (SNRIs) are frequently characterized
as dual-action agents [
55
]. However, the degree to which serotonin and norepinephrine
reuptake is inhibited depends on the dosage. For example, it is evident that venlafaxine
primarily acts as a selective serotonin reuptake inhibitor (SSRI) when given a daily dose of
75 mg [
56
]. At higher dosages, specifically at 225 mg/day and 375 mg/day, venlafaxine
significantly affects the norepinephrine transporter [
9
]. In contrast, lower doses of levomil-
nacipran demonstrate greater efficacy in inhibiting the reuptake of norepinephrine relative
to serotonin, displaying an approximate twofold discrepancy [
57
]. However, it has been
observed that doses of levomilnacipran equal to or exceeding 40 mg per day demonstrate a
significant inhibitory effect on 90 percent of the norepinephrine reuptake and 80 percent of
the serotonin reuptake. All the estimates above were obtained with indirect measures and
the calculation of group means [58].
Pharmaceutical agents that hinder the reuptake of both serotonin and norepinephrine
have exhibited marginally superior effectiveness in the management of unipolar major de-
pression when compared with selective serotonin reuptake inhibitors (SSRIs). A thorough
examination was performed on 93 randomized trials, encompassing a patient population
exceeding 17,000 individuals [
7
]. This analysis aimed to assess and compare the effective-
ness of dual-action agents compared with selective serotonin reuptake inhibitors (SSRIs)
for treating patients. The findings of the study revealed that a more significant percentage
of patients administered dual-action drugs (64 percent) exhibited a favorable response
in comparison with those who received selective serotonin reuptake inhibitors (SSRIs)
Pharmaceuticals 2024,17, 280 12 of 16
(59 percent). Notably, while this disparity showed statistical significance, the magnitude of
the effect was relatively modest [39].
4.2. Pharmacokinetics
4.2.1. Absorption
Duloxetine
Duloxetine was first introduced as a therapeutic option for the management of diabetic
peripheral neuropathy, establishing itself as the first medication to be approved for this
specific condition in the United States [
59
]. Duloxetine has received approval from the Food
and Drug Administration (FDA) for the treatment of major depression, generalized anxiety
disorder, musculoskeletal pain, fibromyalgia, and osteoarthritis since its establishment. As
a result, duloxetine exhibits the most extensive range of approved indications by the Food
and Drug Administration (FDA) compared with other serotonin–norepinephrine reuptake
inhibitors (SNRIs) [
10
]. Duloxetine, in comparison with venlafaxine, has been found to
possess a range of clinical indications for nonpsychiatric conditions, with each indication
corresponding to a specific type of pain syndrome. Duloxetine and venlafaxine demonstrate
structural dissimilarity, as duloxetine is characterized by a chemical structure consisting
of three distinct rings, two of which are near each other. Duloxetine was identified as a
prospective candidate for generic formulation in late 2013 [12].
The following Figure 8illustrates the drug response when compared to placebo to
show the efficacy of duloxetine [12].
Pharmaceuticals 2021, 14, x FOR PEER REVIEW 14 of 18
Figure 8. The efficacy of duloxetine when compared to placebo (as a clinical response) [12], (a,b).
*** p < 0.001, ns = no significance.
4.2.2. Distribution
Duloxetine
The duration of duloxetine’s half-life is approximately 12 h. Even though duloxetine
undergoes metabolism, the resulting metabolites are either short-lived or do not possess
significant biological effects. In other words, the metabolites of duloxetine have minimal
or no substantial clinical activity [60]. The numerical values of 6 and 7 were presented [61].
Duloxetine undergoes primarily hepatic metabolism via the P-450 isoenzyme system,
specifically the 2D6 and 1A2 isoenzymes. This suggests the possibility of drug interactions
and a vulnerability to genetic polymorphism, particularly for the 2D6 isoenzyme. The rec-
ommended dosage is administered once daily [13].
4.2.3. Metabolism
Duloxetine
Duloxetine primarily undergoes hepatic metabolism through two cytochrome P450
isozymes, namely, CYP2D6 and CYP1A2. Pharmacologically inactive metabolites are pre-
sent in the circulation. Duloxetine exhibits moderate inhibition of the cytochrome P450
2D6 enzyme.
4.2.4. Excretion
Duloxetine
It has been observed that food consumption has a moderating impact on the absorp-
tion rate without influencing the extent of absorption. The concurrent administration of
medications with food has been observed to potentially mitigate the incidence of nausea,
a frequently reported adverse effect of serotonin–norepinephrine reuptake inhibitors
(SNRIs). Duloxetine demonstrates resemblances to both selective serotonin reuptake in-
hibitors (SSRIs) and tricyclic antidepressants (TCAs) about its substantial protein binding
capacity, predominant hepatic clearance, and negligible renal excretion, accounting for
Figure 8. The efficacy of duloxetine when compared to placebo (as a clinical response) [
12
], (a,b).
*** p< 0.001, ns = no significance.
4.2.2. Distribution
Duloxetine
The duration of duloxetine’s half-life is approximately 12 h. Even though duloxetine
undergoes metabolism, the resulting metabolites are either short-lived or do not possess
significant biological effects. In other words, the metabolites of duloxetine have minimal or
no substantial clinical activity [60]. The numerical values of 6 and 7 were presented [61].
Duloxetine undergoes primarily hepatic metabolism via the P-450 isoenzyme system,
specifically the 2D6 and 1A2 isoenzymes. This suggests the possibility of drug interactions
and a vulnerability to genetic polymorphism, particularly for the 2D6 isoenzyme. The
recommended dosage is administered once daily [13].
Pharmaceuticals 2024,17, 280 13 of 16
4.2.3. Metabolism
Duloxetine
Duloxetine primarily undergoes hepatic metabolism through two cytochrome P450
isozymes, namely, CYP2D6 and CYP1A2. Pharmacologically inactive metabolites are
present in the circulation. Duloxetine exhibits moderate inhibition of the cytochrome P450
2D6 enzyme.
4.2.4. Excretion
Duloxetine
It has been observed that food consumption has a moderating impact on the absorp-
tion rate without influencing the extent of absorption. The concurrent administration of
medications with food has been observed to potentially mitigate the incidence of nausea, a
frequently reported adverse effect of serotonin–norepinephrine reuptake inhibitors (SNRIs).
Duloxetine demonstrates resemblances to both selective serotonin reuptake inhibitors (SS-
RIs) and tricyclic antidepressants (TCAs) about its substantial protein binding capacity,
predominant hepatic clearance, and negligible renal excretion, accounting for less than 1 per-
cent of the drug in its unaltered state. In contrast, the remaining serotonin–norepinephrine
reuptake inhibitors (SNRIs) demonstrate comparatively reduced levels of protein bind-
ing [
16
]. Moreover, the clearance process of these drugs is significantly influenced by their
elimination via renal excretion [
35
]. Furthermore, a higher percentage of the medication
is eliminated unchanged via the urinary system. As a result, renal disease is more prone
to require dosage modification in administering these serotonin–norepinephrine reuptake
inhibitors (SNRIs) [4,19] As shown in Figure 9[12].
Pharmaceuticals 2021, 14, x FOR PEER REVIEW 15 of 18
less than 1 percent of the drug in its unaltered state. In contrast, the remaining serotonin–
norepinephrine reuptake inhibitors (SNRIs) demonstrate comparatively reduced levels of
protein binding [16]. Moreover, the clearance process of these drugs is significantly influ-
enced by their elimination via renal excretion [35]. Furthermore, a higher percentage of
the medication is eliminated unchanged via the urinary system. As a result, renal disease
is more prone to require dosage modification in administering these serotonin–norepi-
nephrine reuptake inhibitors (SNRIs) [4,19] As shown in Figure 9 [12].
Figure 9. The in vivo metabolism of duloxetine [12].
5. Conclusion
After careful consideration of the past ten years of widespread use of selective sero-
tonin reuptake inhibitors (SSRIs), it is clear that the introduction of SSRIs has not only
brought about a new class of medications but has also shifted our aention toward the
importance of pharmacokinetic properties in the overall functioning of drugs. The essen-
tial aributes of a chemical substance should not be conflated with the pharmacokinetic
properties of a pharmaceutical compound. Differences in traits can manifest in both inter-
individual and intra-individual contexts. To provide safe and effective care to patients,
Figure 9. The in vivo metabolism of duloxetine [12].
Pharmaceuticals 2024,17, 280 14 of 16
5. Conclusions
After careful consideration of the past ten years of widespread use of selective sero-
tonin reuptake inhibitors (SSRIs), it is clear that the introduction of SSRIs has not only
brought about a new class of medications but has also shifted our attention toward the
importance of pharmacokinetic properties in the overall functioning of drugs. The essen-
tial attributes of a chemical substance should not be conflated with the pharmacokinetic
properties of a pharmaceutical compound. Differences in traits can manifest in both inter-
individual and intra-individual contexts. To provide safe and effective care to patients,
clinicians must possess a comprehensive understanding of this phenomenon. While SNRIs
are generally recognized as a distinct category of antidepressants, they exhibit diverse
pharmacological characteristics that contribute to their unique profiles within this class; the
degree to which these variations will lead to notable clinical disparities remains uncertain.
Author Contributions: Methodology, Z.Z. and M.A.; validation, M.A.A.; resources, L.N.T.; data
curation, N.K.; writing—original draft preparation, L.A.-O. and O.A.; writing—review and editing,
W.A.D. and R.A.; supervision, M.H. All authors have read and agreed to the published version of the
manuscript.
Funding: This research received no external funding.
Data Availability Statement: All data are available upon request.
Conflicts of Interest: The authors declare no conflicts of interest.
References
1.
Christensen, M.K.; Lim, C.C.W.; Saha, S.; Plana-Ripoll, O.; Cannon, D.; Momen, N.C.; Whiteford, H.A.; Iburg, K.M.; McGrath, J.J.
The Cost of Mental Disorders: A Systematic Review. Epidemiol. Psychiatr. Sci. 2020,29, e161. [CrossRef]
2.
Ambwani, S.; Dutta, S.; Mishra, G.; Lal, H.; Singh, S.; Charan, J. Adverse Drug Reactions Associated with Drugs Prescribed in
Psychiatry: A Retrospective Descriptive Analysis in a Tertiary Care Hospital. Cureus 2021,13, e19493. [CrossRef] [PubMed]
3.
Malak, M.Z.; Al-amer, R.M.; Khalifeh, A.H.; Jacoub, S.M. Evaluation of Psychological Reactions among Teenage Married Girls in
Palestinian Refugee Camps in Jordan. Soc. Psychiatry Psychiatr. Epidemiol. 2021,56, 229–236. [CrossRef] [PubMed]
4.
Ornoy, A.; Koren, G. Selective Serotonin Reuptake Inhibitor Use in Pregnant Women; Pharmacogenetics, Drug-Drug Interactions
and Adverse Effects. Expert. Opin. Drug Metab. Toxicol. 2018,14, 247–259. [CrossRef]
5.
Spigset, O. Adverse Reactions of Selective Serotonin Reuptake Inhibitors: Reports from a Spontaneous Reporting System. Drug
Saf. 1999,20, 277–287. [CrossRef] [PubMed]
6.
Maideen, N.M.P.; Rajkapoor, B.; Muthusamy, S.; Ramanathan, S.; Thangadurai, S.A.; Sughir, A.A. A Review on Pharmacokinetic
and Pharmacodynamic Drug Interactions of Adrenergic
β
-Blockers with Clinically Relevant Drugs-An Overview. Curr. Drug
Metab. 2021,22, 672–682. [CrossRef]
7.
Oliveira, P.; Ribeiro, J.; Donato, H.; Madeira, N. Smoking and Antidepressants Pharmacokinetics: A Systematic Review. Ann. Gen.
Psychiatry 2017,16, 17. [CrossRef] [PubMed]
8.
Kuzin, M.; Schoretsanitis, G.; Haen, E.; Ridders, F.; Hiemke, C.; Gründer, G.; Paulzen, M. Pharmacokinetic Interactions between
Clozapine and Sertraline in Smokers and Non-Smokers. Basic. Clin. Pharmacol. Toxicol. 2020,127, 303–308. [CrossRef]
9.
Lochmann, D.; Richardson, T. Selective Serotonin Reuptake Inhibitors. In Handbook of Experimental Pharmacology; Springer New
York LLC: New York, NY, USA, 2019; Volume 250, pp. 135–144.
10.
Mandrioli, R.; Protti, M.; Mercolini, L. New-Generation, Non-SSRI Antidepressants: Therapeutic Drug Monitoring and Pharmaco-
logical Interactions. Part 1: SNRIs, SMSs, SARIs. Curr. Med. Chem. 2017,25, 772–792. [CrossRef]
11.
Huddart, R.; Hicks, J.K.; Ramsey, L.B.; Strawn, J.R.; Smith, D.M.; Bobonis Babilonia, M.; Altman, R.B.; Klein, T.E. PharmGKB
Summary: Sertraline Pathway, Pharmacokinetics. Pharmacogenet Genom. 2020,30, 26–33. [CrossRef]
12.
Lampropoulou, D.I.; Lioliou, K.; Zerva, E.; Madia, X.; Vardoulaki, D.; Aravantinos, G.; Filippou, D.; Gazouli, M. CDK4/6
Inhibitors and SSRIs/SNRIs: A Brief Review of Their Safety Profiles Focusing on Potential Drug Interactions. Top. Biomed. Res.
Educ. 2023,1, 24–32.
13.
Eugene, A.R. Optimizing Drug Selection in Psychopharmacology Based on 40 Significant CYP2C19- And CYP2D6-Biased Adverse
Drug Reactions of Selective Serotonin Reuptake Inhibitors. PeerJ 2019,7, e7860. [CrossRef]
14.
Kowalska, M.; Nowaczyk, J.; Fijałkowski, Ł.; Nowaczyk, A. Paroxetine—Overview of the Molecular Mechanisms of Action. Int. J.
Mol. Sci. 2021,22, 1662. [CrossRef]
15.
Colombo, A.; Giordano, F.; Giorgetti, F.; Di Bernardo, I.; Bosi, M.F.; Varinelli, A.; Cafaro, R.; Pileri, P.; Cetin, I.; Clementi, E.; et al.
Correlation between Pharmacokinetics and Pharmacogenetics of Selective Serotonin Reuptake Inhibitors and Selective Serotonin
and Noradrenaline Reuptake Inhibitors and Maternal and Neonatal Outcomes: Results from a Naturalistic Study in Patients with
Affec. Hum. Psychopharmacol. 2021,36, e2772. [CrossRef]
Pharmaceuticals 2024,17, 280 15 of 16
16.
de Leon, J.; Spina, E. Possible Pharmacodynamic and Pharmacokinetic Drug-Drug Interactions That Are Likely to Be Clinically
Relevant and/or Frequent in Bipolar Disorder. Curr. Psychiatry Rep. 2018,20, 17. [CrossRef] [PubMed]
17.
Edinoff, A.N.; Fort, J.M.; Woo, J.J.; Causey, C.D.; Burroughs, C.R.; Cornett, E.M.; Kaye, A.M.; Kaye, A.D. Selective Serotonin
Reuptake Inhibitors and Clozapine: Clinically Relevant Interactions and Considerations. Neurol. Int. 2021,13, 445–463. [CrossRef]
[PubMed]
18.
Sawyer, E.K.; Howell, L.L. Pharmacokinetics of Fluoxetine in Rhesus Macaques Following Multiple Routes of Administration.
Pharmacology 2011,88, 44. [CrossRef] [PubMed]
19.
Ahmed, A.T.; Biernacka, J.M.; Jenkins, G.; Rush, A.J.; Shinozaki, G.; Veldic, M.; Kung, S.; Bobo, W.V.; Hall-Flavin, D.K.;
Weinshilboum, R.M.; et al. Pharmacokinetic-Pharmacodynamic Interaction Associated with Venlafaxine-XR Remission in Patients
with Major Depressive Disorder with History of Citalopram / Escitalopram Treatment Failure. J. Affect. Disord. 2019,246, 62–68.
[CrossRef] [PubMed]
20.
Kazmi, F.; Hensley, T.; Pope, C.; Funk, R.S.; Loewen, G.J.; Buckley, D.B.; Parkinson, A. Lysosomal Sequestration (Trapping) of
Lipophilic Amine (Cationic Amphiphilic) Drugs in Immortalized Human Hepatocytes (Fa2N-4 Cells). Drug Metab. Dispos. 2013,
41, 897. [CrossRef] [PubMed]
21.
Bolo, N.R.; Hodé, Y.; Nédélec, J.F.; Lainé, E.; Wagner, G.; MacHer, J.P. Brain Pharmacokinetics and Tissue Distribution In Vivo
of Fluvoxamine and Fluoxetine by Fluorine Magnetic Resonance Spectroscopy. Neuropsychopharmacology 2000,23, 428–438.
[CrossRef] [PubMed]
22.
Vashistha, V.K.; Sethi, S.; Tyagi, I.; Das, D.K. Chirality of Antidepressive Drugs: An Overview of Stereoselectivity. Asian Biomed
(Res. Rev. News) 2022,16, 55. [CrossRef] [PubMed]
23.
Kawai, H.; Machida, M.; Ishibashi, T.; Kudo, N.; Kawashima, Y.; Mitsumoto, A. Chronopharmacological Analysis of Antidepres-
sant Activity of a Dual-Action Serotonin Noradrenaline Reuptake Inhibitor (SNRI), Milnacipran, in Rats. Biol. Pharm. Bull. 2018,
41, 213–219. [CrossRef] [PubMed]
24.
Spina, E.; Barbieri, M.A.; Cicala, G.; Bruno, A.; de Leon, J. Clinically Relevant Drug Interactions between Newer Antidepressants
and Oral Anticoagulants. Expert. Opin. Drug Metab. Toxicol. 2020,16, 31–44. [CrossRef]
25.
Tasker, T.C.G.; Bye, C.M.; Zussman, B.D.; Link, C.G.G. Paroxetine Plasma Levels: Lack of Correlation with Efficacy or Adverse
Events. Acta Psychiatr. Scand. Suppl. 1989,350, 152–155. [CrossRef]
26.
Hiemke, C.; Härtter, S. Pharmacokinetics of Selective Serotonin Reuptake Inhibitors. Pharmacol. Ther. 2000,85, 11–28. [CrossRef]
27. Irons, J. Fluvoxamine in the Treatment of Anxiety Disorders. Neuropsychiatr. Dis. Treat. 2005,1, 289.
28.
Hiemke, C. Paroxetine: Pharmacokinetics and Pharmacodynamics. Fortschr. Neurol. Psychiatr. 1994,62 (Suppl. S1), S2–S8.
[CrossRef]
29.
Serretti, A.; Calati, R.; Massat, I.; Linotte, S.; Kasper, S.; Lecrubier, Y.; Sens-Espel, R.; Bollen, J.; Zohar, J.; Berlo, J.; et al. Cytochrome
P450 CYP1A2, CYP2C9, CYP2C19 and CYP2D6 Genes Are Not Associated with Response and Remission in a Sample of
Depressive Patients. Int. Clin. Psychopharmacol. 2009,24, 250–256. [CrossRef]
30.
Fatunde, O.A.; Brown, S.A. The Role of CYP450 Drug Metabolism in Precision Cardio-Oncology. Int. J. Mol. Sci. 2020,21, 604.
[CrossRef]
31. Hurst, M.; Lamb, H.M. Fluoxetine. CNS Drugs 2000,14, 51–80. [CrossRef]
32.
Altamura, A.C.; Moro, A.R.; Percudani, M. Clinical Pharmacokinetics of Fluoxetine. Clin. Pharmacokinet. 1994,26, 201–214.
[CrossRef] [PubMed]
33.
Malak, M.Z.; Shuhaiber, A.H.; Alsswey, A.; Tarawneh, A. Social Support as the Mediator for the Relationship between Internet
Gaming Disorder and Psychological Problems among University Students. J. Psychiatr. Res. 2023,164, 243–250. [CrossRef]
34.
Deodhar, M.; Al Rihani, S.B.; Darakjian, L.; Turgeon, J.; Michaud, V. Assessing the Mechanism of Fluoxetine-Mediated CYP2D6
Inhibition. Pharmaceutics 2021,13, 148. [CrossRef]
35. Boguta, P.; Juchnowicz, D.; Wróbel-Knybel, P.; Biała-K ˛edra, A.; Karakuła-Juchnowicz, H. Safety of Concomitant Treatment with
Non-Vitamin K Oral Anticoagulants and SSRI/SNRI Antidepressants. Curr. Probl. Psychiatry 2018,19, 267–278. [CrossRef]
36.
LLerena, A.; Dorado, P.; Berecz, R.; González, A.P.; Peñas-LLedó, E.M. Effect of CYP2D6 and CYP2C9 Genotypes on Fluoxetine
and Norfluoxetine Plasma Concentrations during Steady-State Conditions. Eur. J. Clin. Pharmacol. 2004,59, 869–873. [CrossRef]
37.
Mikami, A.; Ohtani, H.; Hori, S.; Sawada, Y. Pharmacokinetic Model Incorporating Mechanism-Based Inactivation of CYP2D6
Can Explain Both Non-Linear Kinetics and Drug Interactions of Paroxetine. Int. J. Clin. Pharmacol. Ther. 2013,51, 374–382.
[CrossRef] [PubMed]
38.
Pasi, P.; Kröll, D.; Siegfried, A.; Sykora, M.; Wildisen, A.; Milone, C.; Milos, G.; Horka, L.; Fischli, S.; Henzen, C. Plasma
Concentrations of SSRI/SNRI after Bariatric Surgery and the Effects on Depressive Symptoms. Front. Psychiatry 2023,14, 1132112.
[CrossRef] [PubMed]
39.
Strawn, J.R.; Vaughn, S.; Ramsey, L.B. Pediatric Psychopharmacology for Depressive and Anxiety Disorders. Focus 2022,
20, 184–190. [CrossRef]
40.
Rendi´c, S.P.; Crouch, R.D.; Guengerich, F.P. Roles of Selected Non-P450 Human Oxidoreductase Enzymes in Protective and Toxic
Effects of Chemicals: Review and Compilation of Reactions. Arch. Toxicol. 2022,96, 2145–2246. [CrossRef]
41. Bourin, M.; Chue, P.; Guillon, Y. Paroxetine: A Review. CNS Drug Rev. 2001,7, 25–47. [CrossRef]
42.
Kaye, C.M.; Haddock, R.E.; Langley, P.F.; Mellows, G.; Tasker, T.C.G.; Zussman, B.D.; Greb, W.H. A Review of the Metabolism
and Pharmacokinetics of Paroxetine in Man. Acta Psychiatr. Scand. 1989,80, 60–75. [CrossRef]
Pharmaceuticals 2024,17, 280 16 of 16
43.
Porcelli, S.; Drago, A.; Fabbri, C.; Gibiino, S.; Calati, R.; Serretti, A. Pharmacogenetics of Antidepressant Response. J. Psychiatry
Neurosci. 2011,36, 87–113. [CrossRef] [PubMed]
44.
Buoli, M.; Caldiroli, A.; Serati, M. Pharmacokinetic Evaluation of Pregabalin for the Treatment of Generalized Anxiety Disorder.
Expert. Opin. Drug Metab. Toxicol. 2017,13, 351–359. [CrossRef] [PubMed]
45.
Armah, F.A.; Henneh, I.T.; Amponsah, I.K.; Biney, R.P.; Malcolm, F.; Alake, J.; Ahlidja, W.; Ahmed, M.A.; Adokoh, C.K.; Adukpo,
G.E.; et al. Antidepressant and Anxiolytic Effects and Subacute Toxicity of the Aerial Parts of Psychotria Ankasensis J.B.Hall
(Rubiaceae) in Murine Models. Evid.-Based Complement. Altern. Med. 2021,2021, 5543320. [CrossRef]
46.
Gillman, P.K. Tricyclic Antidepressant Pharmacology and Therapeutic Drug Interactions Updated. Br. J. Pharmacol. 2007,151, 737.
[CrossRef] [PubMed]
47.
Edinoff, A.N.; Akuly, H.A.; Hanna, T.A.; Ochoa, C.O.; Patti, S.J.; Ghaffar, Y.A.; Kaye, A.D.; Viswanath, O.; Urits, I.; Boyer, A.G.;
et al. Selective Serotonin Reuptake Inhibitors and Adverse Effects: A Narrative Review. Neurol. Int. 2021,13, 387–401. [CrossRef]
48.
Perrotta, C.; Giordano, F.; Colombo, A.; Carnovale, C.; Castiglioni, M.; Di Bernardo, I.; Giorgetti, F.; Pileri, P.; Clementi, E.; Viganò,
C. Postpartum Bleeding in Pregnant Women Receiving SSRIs/SNRIs: New Insights from a Descriptive Observational Study and
an Analysis of Data from the FAERS Database. Clin. Ther. 2019,41, 1755–1766. [CrossRef] [PubMed]
49. Pinninti, N.R.; de Leon, J. Interaction of Sertraline with Clozapine. J. Clin. Psychopharmacol. 1997,17, 119–120. [CrossRef]
50.
Mrazek, D.A.; Biernacka, J.M.; O’Kane, D.J.; Black, J.L.; Cunningham, J.M.; Drews, M.S.; Snyder, K.A.; Stevens, S.R.; Rush, A.J.;
Weinshilboum, R.M. CYP2C19 Variation and Citalopram Response. Pharmacogenet Genomics 2011,21, 1–9. [CrossRef]
51.
Hiemke, C. Consensus Guideline Based Therapeutic Drug Monitoring (TDM) in Psychiatry and Neurology. Curr. Drug Deliv.
2016,13, 353–361. [CrossRef]
52.
Spina, E.; Trifirò, G.; Caraci, F. Clinically Significant Drug Interactions with Newer Antidepressants. CNS Drugs 2012,26, 39–67.
[CrossRef] [PubMed]
53.
Perahia, D.G.; Bangs, M.E.; Zhang, Q.; Cheng, Y.; Ahl, J.; Frakes, E.P.; Adams, M.J.; Martinez, J.M. The Risk of Bleeding with
Duloxetine Treatment in Patients Who Use Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Analysis of Placebo-Controlled
Trials and Post-Marketing Adverse Event Reports. Drug Healthc. Patient Saf. 2013,5, 211–219. [CrossRef]
54.
Ungvari, Z.; Tarantini, S.; Yabluchanskiy, A.; Csiszar, A. Potential Adverse Cardiovascular Effects of Treatment with Fluoxetine
and Other Selective Serotonin Reuptake Inhibitors (SSRIs) in Patients With Geriatric Depression: Implications for Atherogenesis
and Cerebromicrovascular Dysregulation. Front. Genet. 2019,10, 455576. [CrossRef] [PubMed]
55.
Strawn, J.R.; Poweleit, E.A.; Ramsey, L.B. CYP2C19-Guided Escitalopram and Sertraline Dosing in Pediatric Patients: A Pharma-
cokinetic Modeling Study. J. Child. Adolesc. Psychopharmacol. 2019,29, 340–347. [CrossRef] [PubMed]
56.
Laux, G. Serotonin Reuptake Inhibitors: Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, and Sertraline.
In NeuroPsychopharmacotherapy; Springer International Publishing: Berlin/Heidelberg, Germany, 2022; pp. 1257–1269,
ISBN 9783030620592.
57.
Citrome, L. Levomilnacipran for Major Depressive Disorder: A Systematic Review of the Efficacy and Safety Profile for This
Newly Approved Antidepressant—What Is the Number Needed to Treat, Number Needed to Harm and Likelihood to Be Helped
or Harmed? Int. J. Clin. Pract. 2013,67, 1089–1104. [CrossRef]
58.
McIntyre, R.S. The Role of New Antidepressants in Clinical Practice in Canada: A Brief Review of Vortioxetine, Levomilnacipran
ER, and Vilazodone. Neuropsychiatr. Dis. Treat. 2017,13, 2913–2919. [CrossRef]
59.
Sloan, G.; Alam, U.; Selvarajah, D.; Tesfaye, S. The Treatment of Painful Diabetic Neuropathy. Curr. Diabetes Rev. 2022,
18, e070721194556. [CrossRef]
60.
Hsu, E.S. Acute and Chronic Pain Management in Fibromyalgia: Updates on Pharmacotherapy. Am. J. Ther. 2011,18, 487–509.
[CrossRef]
61.
Poweleit, E.A.; Cinibulk, M.A.; Novotny, S.A.; Wagner-Schuman, M.; Ramsey, L.B.; Strawn, J.R. Selective Serotonin Reuptake
Inhibitor Pharmacokinetics During Pregnancy: Clinical and Research Implications. Front. Pharmacol. 2022,13, 833217. [CrossRef]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual
author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to
people or property resulting from any ideas, methods, instructions or products referred to in the content.