1. The major metabolic pathways of sertraline have been established in animal studies and are
presumed to be similar in humans. They are shown in figure 1. The metabolism of sertraline
has been studied in the rat and dog using [14C]sertraline ad ministration. Mass balance
studies were conducted using urinary, biliary and faecal drug excretion. Elimination of
sertraline proceeds by hepatic me tabolism to oxidated and glucuronidated metabo lites (De
Vane et al., 2002). Clinical pharmacokinetics of sertraline
2. From studies on animals, the main metabolic routes of sertraline have been identified to be
similar in human in terms of processes. Figure 1 depicts the processes. Utilizing [ 14C]
sertraline administration, the metabolism of sertraline has been explored in the dog and rat.
The excretion of sertraline via faeces, urine and bile was determined using mass balance
experiments. After undergoing glucuronidation and oxidation, sertraline is excreted from the
body via hepatic metabolism to produce metabolites (De Vane et al., 2002).
3.
4. Metabolism–Sertraline undergoes
6. Other metabolic pathways of
extensive first pass metabolism. The
sertraline result in the formation of
principal initial pathway of
sertraline carbamic acid, N
metabolism for sertraline is Nhydroxy- sertraline and the
demethylation. N deaminated ketone of sertraline
desmethylsertraline has a plasma
(figure 1). These metabolites are
terminal elimination half-life of 62
conju gated with glucuronic acid
to 104 hours. Both in vitro
and undergo biliary and urinary
biochemical and in vivo
excretion, accounting overall for
pharmacological testing have shown
82% of radioactivity excreted in the
N-desmethylsertraline to be
bile and urine of dogs following
substantially less active than
administration of [14C ]sertraline.
sertraline. Both sertraline and N[6] Clinical pharmacokinetics of
desmethylsertraline undergo
sertraline
oxidative deamination and
7.
subsequent reduction,
hydroxylation, and glucuronide
conjugation. Sertraline
hydrochloride
5.
8. Sertraline, a commonly prescribed medication, undergoes extensive first-pass
metabolism. The primary initial pathway involves N-demethylation, leading to the
formation of N-desmethylsertraline. However, it is worth noting that Ndesmethylsertraline is considerably less active than sertraline, as demonstrated by
both in vitro biochemical and in vivo pharmacological testing. The plasma terminal
elimination half-life of N-desmethylsertraline ranges from 62 to 104 hours (Food
and Drug Administration, 2012).
9. Considerable first-pass metabolism is experienced by a common prescription drug
known as sertraline. N-demethylation, which creates N-desmethylsertraline, is the
primary early metabolic route. As shown by both real-life pharmacological
assessments and laboratory-based biochemical research, sertraline, but, is more
potent than N-demethylsertraline. Therefore, it should be emphasized. Ranging
from 62 to 104 hours, N-desmethylsertraline has an elimination half-life in the
plasma terminal (Food and Drug Administration, 2012).
10. In addition to N-demethylation, sertraline and N-desmethylsertraline undergo
further metabolic transformations (Food and Drug Administration, 2012). These
include oxidative deamination, subsequent reduction, hydroxylation, and
glucuronide conjugation. These processes result in the formation of metabolites
such as sertraline carbamic acid, N-hydroxy-sertraline, and the deaminated ketone
of sertraline. These metabolites are then conjugated with glucuronic acid and
eliminated from the body via biliary and urinary excretion. In fact, they account for
approximately 82% of the radioactivity excreted in the bile and urine of dogs
following the administration of sertraline.
11. Along with N-demethylation, other metabolic pathways are gone through by
sertraline and its metabolite. These routed include oxidation deamination, before
reduction, hydroxylation, and glucuronide conjugation. Including named
deaminated ketone of sertraline, sertraline carbamic acid, and N-hydroxysertraline, via reactions, those by-products are created (De Vane et al., 2002). Later,
glucuronic acid is mixed with those metabolites and undergo excretion via the
urine and bile. Approximately 82% of the radioactive compounds in the urine and
bila of sertraline-treated dogs, these metabolites are accounted for (Tremaine et
al.,1989, as cited in De Vane et al., 2002).
12. Overall, the metabolism of sertraline involves multiple pathways, including Ndemethylation and subsequent transformations leading to the formation of various
metabolites. While N-desmethylsertraline is less active than the parent compound,
the other metabolites, including sertraline carbamic acid, N-hydroxy-sertraline, and
the deaminated ketone, contribute significantly to the elimination of sertraline from
the body.
13. Counting N-demethylation, sertraline goes through a number of metabolic
reactions, which creates an abundant of metabolites. The body’s elimination of
sertraline needs other metabolites like deaminated ketone, sertraline carbamic acid,
and N-hydro-sertraline, despite the fact that the parent compound is more potent
compared to N-desmethylsertraline (Food and Drug Administration, 2012),
14. Multiple cytochrome P450 (CYP) isoforms ap pear to be responsible for the metabolism of
sertraline.[ 32] The role of CYP2C19 in sertraline N-demethylation was investigated in
human microsomes of six extensive and three poor meta bolisers.[ 33] This in vitro study
found only CYP- 2C8/9 and CYP2C19 to be substantially affected by CYP inhibitors and/or
CYP antibodies. The for mation of DMS was also significantly slower in CYP2C19 poor
metabolisers.[ 33] Minimal effect on sertraline demethylation was observed with the
inhibition of CYP1A2, 2A6, 2D6, 2E1 or 3A4/5. Other reports have shown sertraline Ndemethyla tion to be more interspersed among different CYP isoforms in vitro by taking into
account the relative abundance of each CYP isoform. [32,34] Clinical pharmacokinetics of
sertraline
15. In the metabolism of sertraline, a number of isoforms of cytochrome P450 (CYP) is called for
(Greenblatt et al.,1999, as claimed in De Vane et al., 2002). Human microsomes from three
resondents with limited metabolism and six respondents with extensive metabolism were
utilized to explore the role of the certain isoform CYP2C19 in the N-demethylation of
sertraline (Xu et al., 1999, as cited in De Vane et al., 2002). In conjunction with an in vitro
study, CYP inhibitors and/or CYP antibodies affected only the CYP2C19 and CYP-2C8/9
enzymes. People with low rate of CYP2C19-mediated metabolism showed slow production of
DMS (N-desmethylsertraline) (Xu et al., 1999, as written in De Vane et al., 2002). The
inhibition of CYP2E1, 1A2, 3A4/5, 2A6 or 2D6 did not significantly impact the
demethylation of sertraline. In a variety of CYP isoforms, the N-demethylation of sertraline
may happen in a variety of CYP isoforms, in accordance with in vitro studies that took into
account the relative abundance of every CYP isoform (Greenblatt et al., 1999; Kobayashi et
al., 1999, as claimed in De Vane et al., 2002).
16. Sertraline was shown to be N-demethylated by several CYP enzymes in human microsomes
and cDNA-expressed human CYP isoforms, including CYP2D6, CYP2C9, CYP2B6,
CYP2C19 and CYP3A4. Among these five isoforms, CYP2D6 had the highest estimated
intrinsic clearance (max imum velocity/Michaelis constant; Vmax/Km) of µg/ 0.309
17.
18.
19.
20.
21.
22.
min/pmol. The percentage contribution of each isoform relative to Vmax/Km values was 35,
29, 14, 13 and 9% for CYP2D6, CYP2C9, CYP2B6, CYP2C19 and CYP3A4, respectively.
[34] Clinical pharmacokinetics of sertraline
Eventhough a variety of CYP enzymes determined in cDNA-expressed human CYP isoforms
and human microsomes, sertraline is N-demethylated. The CYP3A4, CYP2D6, CYP2B6,
CYP2C9, and CYP2C19 enzymes are among those participated. With a value of 0.309
µg/min/pmol, CYP2D6 had the maximum approximated intrinsic clearance (maximum
velocity/Michaelis constant; Vmax/Km) of the group. For CYP2D6, CYP2C9, CYP2B6,
CYP2C19, and CYP3A4, the contribution of each isoform to the Vmax/Km values was
around 35%, 29%, 14%, 13%, and 9%, respectively [34]. (Kobayashi et al., 1999, as cited in
De Vane et al., 2002)
Previously, sertraline metabolism was reported to be unaffected when compared between poor
and extensive CYP2D6 metabolisers. [35] This finding is not surprising, since CYP2D6
accounts for ap proximately 3% of the liver’s CYP activity and several CYP enzymes
presumably metabolise sertraline in vivo.[ 32] Given the modest contribu tion of each isoform
to the N-demethylation of sertraline in vitro, [33] alternative pathways could compensate in
subjects genetically deficient for CYP2D6 metabolising activity. Recently, in a hu man study
using six poor metabolisers and six ex tensive metabolisers of the CYP2C19 gene, the oral
clearance (CL/F) of sertraline was significantly lower in the poor metabolisers. [36] Clinical
pharmacokinetics of sertraline
Comparing respondents with low and extensive CYP2D6 metabolizing capacity, the
metabolism of sertraline formerly observed to be unaltered (Hamelin et al., 1996, as claimed
in De Vane et al., 2002). The fact is not unexpected, since only estimate 3% of the liver’s
CYP activity is pitched in by CYP2D6, and several other CYP enzymes are made use of by
the body to metabolize sertraline (Greenblatt et al., 1999, as written in De Vane et al., 2002).
Individuals with a hereditary CYP2D6 activity impairment may be able to compensate via
other pathways, despite the fact that the contribution of every isoform to the N-demethylation
of sertraline in laboratory experiment was minimum (Xu et al., 1999, as reported in De Vane
et al., 2002). Compared to individuals with better metabolizers, those with worse CYP2C19
gene metabolizers had considerably lower oral clearance (CL/F), which was shown in a latest
human study [36] (Wang, 2001, as cited in De Vane et al., 2002).
The major metabolite, DMS, is modestly phar macologically active in vitro[ 37] and in
vivo.[ 22] Re ceptor binding profiles in human brain using [3H] citalopram and [3H]serotonin
have shown in hibition at these receptors by sertraline to be 25- to 60-fold greater than for
DMS.[ 5] Table III summa rises in vitro serotonin receptor inhibitory values for sertraline and
DMS in comparisons with other SSRIs. 5,22,37-39] Clinical pharmacokinetics of sertraline
Both in vitro [37] (Bolden-Watson & Richelson, 1993, as cited in De Vane et al., 2002)and in
vivo [22] (Fuller et al., 1995, as claimed in De Vane et al., 2002), DMS, the main metabolite
of sertraline, has a modest level or pharmacological action. Sertraline has 25-60 times more
inhibitory effects on these receptors compared to DMS, shown by investigation using [3H]
serotonin and [3H] citalopram to examine receptor binding in the human brain [5] (Owens et
al., 1997, as reported in De Vane et al., 2002). An overview of the serotonin receptor
inhibitory values for DMS and sertraline in comparison to other SSRIs is given by Table III,
in conjunction with in vitro studies (Bolden-Watson & Richelson, 1993; Cusack et al., 1994;
Fuller et al., 1995; Owens et al., 1997; Sprouse, 1996, as stated in De Vane et al.,
2002)[5,22,37-39]
In studies analysing animal brain tissue and hu man plasma, concentrations of DMS were
greater than those of sertraline.[ 20,22] Under steady-state administration conditions, plasma
concentrations of sertraline have varied widely, nearly 15-fold, between individuals receiving
the same daily dose. 20] This variability is consistent with the known interindividual CYP
isoenzyme activity in humans and the assumption that multiple CYP isoforms appear to be
involved in the metabolism of sertraline.[ 32,34] The ratio of DMS to sertraline varied from
1.1–4.1 among 27 patients receiving sertraline 100–300 mg/day. [20] All patients had a higher
DMS concentration in plasma compared with parent drug. The mean and range of steady state
sertraline plasma concentrations from a pro gram of therapeutic drug monitoring are shown in
figure 3 and figure 4. Clinical pharmacokinetics of sertraline
23.
24. Congruent with a higher plasma concentration of DMS than of sertraline, the mean
elimination half-life of DMS exceeded that of sertraline in most reports. A summary of the
pharmacokinetic parameters for DMS is given in table IV. In mice, brain DMS concentrations
were nearly as high fol lowing parenteral sertraline administration as they mans. were
following DMS administration. The admin istration of preformed DMS was found to decrease
the brain concentration of 5-hydroxyindoleacetic acid (5-HIAA). 5-HIAA concentration
serves as a measurement of brain serotonin turnover as a con sequence of inhibiting the
serotonin transporter. This finding in rats suggests that DMS contributes to serotonin reuptake
inhibition.[ 22] A separate study found no effect of DMS on serotonin reup take in rats. [39]
DMS appeared to have 5–10% of the potency of sertraline on serotonin uptake inhi bition.[ 5]
Although DMS has been regarded as lacking antidepressant activity, these observations
suggest that DMS contributes modestly to the overall pharmacological effects of sertraline in
humans. DMS is the only metabolite reported to be pharmacologically active and the only
metabolite whose concentration has been reported in human pharmacokinetic studies. An
unequivocal assess ment of whether DMS is an antidepressant in hu mans would require
direct administration of DMS. Clinical pharmacokinetics of sertraline
25.
26.