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New Horizons in Science & Technology (NHS&T), Volume 1(2):27-32 ISSN 1929-2015 (Online) International Network for Scientific & Industrial Information Recent Studies on Pharmacokinetic of Citalopram and Therapeutic Drug Monitoring Zuhal Uckun
Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Ankara University, Tandogan-06100, Ankara,
Corresponding author: [email protected]ABSTRACT Citalopram (CIT) is a potent and selective serotonin reuptake inhibitor in the central nervous system and widely used to treat depression. There are some factors that affect the pharmacokinetics of citalopram, for example age, renal and hepatic insufficiency, genetic polymorphism. The most important factor among them is genetic polymorphism; which can change plasma concentrations of CIT and its metabolites. Therapeutic drug monitoring (TDM) provides indirect measurement of drug concentration at the effector site, -plasma concentration of any drug reflect concentration at the site of action. Therefore, TDM can be used by the physicians to optimize dosage decisions, but only with a drug level in blood may always not help to reach a decisive conclusion. TDM results should be supported by analysis of genotype. In line with this objective, this study reports a brief review about pharmacokinetic of citalopram and therapeutic drug monitoring. Key words: Therapeutic drug monitoring, citalopram, pharmacokinetic New Horizons in Science & Technology 1(2):27-32 INTRODUCTION
bioavability is reported to be approximately 80%
Citalopram (1-[3-(dimethylamino) propyl]-
(Bezchlibnyk-Butler et al., 2000; Hiemke and
1- (4 - fluorophenyl) - 1, 3- dihydroisobenzofuran-
Hartter, 2000). CIT is bound to protein in 80%
5carbonitrile; CIT) is a bicyclic phthalate compound
(Milne and Goa, 1991) and thus interacts at specific
approved in 1998 by the US Food and Drug
protein-binding sites quite unlikely. It is widely
Administration for the treatment of depression
distributed among peripheral tissues, with the volume
(Pollock, 2001). It is also proposed for the other
of distribution of CIT, which is approximately
central nervous system diseases such as anxiety,
between 12 and 16 L/kg (Milne and Goa, 1991). CIT
obsessive-compulsive disorders, bipolar disorders
displays linear kinetics over the therapeutic dosage
and various phobias (Pollock, 2001). CIT is marketed
range of 10-60 mg/day, and peak plasma levels occur
as a racemic compounds, which are both S-(+) and R-
2 to 4 hours after single or multiple doses (Baumann
(-) enantiomers. The S-(+) enantiomer of CIT is
pharmacologically active in relation to inhibition of
serotonin reuptake versus the R-(-) enantiomer of
CIT (Bezchlibnyk-Butler et al., 2000). Citalopram
CIT is metabolized in liver by two N-
has by far the highest selectivity for inhibiting
demethylation steps, to demethylcitalopram (DCIT)
serotonin reuptake over noradrenaline reuptake
(Hiemke and Hartter, 2000; Owens et al., 2001).
didemethylationcitalopram (DDCIT) by CYP2D6.
Selective serotonin reuptake inhibitors (SSRIs) act by
inhibiting the reuptake of serotonin into the the
metabolites of the proponic acid derivative (CIT-
presynaptic nerve terminal, enhancing synaptic
PROP) and CIT-N-oxide occurs by oxidative
deamination and by N-oxide, respectively (Gutierrez
and Abramowitz, 2000, Unceta et al., 2011) (Figure
detectable in the substantial amounts (Bezchlibnyk-Butler et al., 2000; Baumann and Larsen, 1995). The
Absorption and Distribution
enhanced hydrophilicity of the metabolites limits
CIT is well absorbed from gastrointestinal
their ability to cross the blood-brain barrier.
tract after oral administration. In contrast to the other
Therefore, the metabolites of CIT are of minor
SSRIs, the first-pass effect of CIT seems to be of
minor importance, and for this reason, its oral
New Horizons in Science & Technology 1(2):27-32
significant difference between two age groups
Lima et al. (2005) reported the mean plasma
elimination. The distribution phase continues
levels of CIT corrected for a 20 mg daily dose were
approximately 10 hours. The elimination half-life
55% higher in the very elderly patients (>=80 year,
(t1/2) has been determined to vary between 30 and 35
n=23) (65±30 ng/ml; p<0.001) and 38% higher in the
hours for CIT, 50 hours for DCIT and 100 hours for
elderly patients (65-79 year, n=57) (58±24 ng/ml;
DDCIT (Baumann and Larsen, 1995). CIT can be
p<0.001) when compared to the adult patients (=<64
administered once daily due to its relatively long
year, n=48) (42±17 ng/ml). DCIT mean plasma level
half-life (Bezchlibnyk-Butler et al., 2000). 20% of the
was 38% higher (p<0.05) in the very elderly patients
dose CIT is excreted unchanged in the urine (Joubert
(22±10 ng/ml) when compared to the adult patients
and Stein, 1999; Pollock, 2001). CIT and its
(16±9 ng/ml). The mean plasma concentration of CIT
metabolites are cleared primarily by the kidneys.
+ DCIT was 48% higher in the very elderly patients
Renal clearance is estimated at 2.3 to 3.3 L per hour,
(86±36 ng/ml; p<0.001) and 33% higher in the
and systemic clearance ranges from 23 to 28 L per
elderly patients (77±28 ng/ml; p<0.001) when
hour (Noble and Benfield, 1997). Summary of
compared to the adult patients (58±21 ng/ml).
pharmacokinetic properties of citalopram is given in
As a consequence, the studies above suggest
that there are age-related pharmacokinetic effects.
Therefore, it is recommended that elderly patients
Table 1. Summary of pharmacokinetic properties of Property Hepatic and Renal insufficiency
clearance of citalopram was reduced by 17%, and t1/2
was moderately increased; the peak plasma
concentration was unaffected in patients with mild to
moderate renal function impairment compared to
normal subjects. In these patients, dosage adjustment
is not recommended. Also, Joffe et al. (1998)
reported oral clearance of citalopram was decreased
by 37% and t1/2 had doubled in patients with impaired
aAdapted from Baumann and Larsen, 1995; Noble and Benfield,
hepatic function compared to normal subjects; the
1997; Joubert, A.F. and Stein, 1999; Bezchlibnyk-Butler et al., 2000.
peak plasma concentration was unaffected. It is
recommended that patients with reduced liver
FACTORS ALTERING THE PHARMA-
function should receive lower initial doses.
COKINETIC OF CITALOPRAM Genetic polymorphisms in genes that encode enzymes involved in metabolism of citalopram
citalopram are as follows; age, hepatic and renal
insufficiency and genetic polymorphisms in genes
citalopram are CYP2C19, CYP3A4 and CYP2D6.
that encode enzymes involved in metabolism.
Major metabolite of CIT is DCIT. Therefore,
mutations in CYP2C19 and CYP3A4 genes are more
important than those in CYP2D6 gene.
Today, there are around 27 variant allele of
subjects aged more than 60 years that CIT the area
CYP2C19 and around 22 variant allele of CYP3A4
under the dose concentration curve (AUC) and half-
life were increased in a single –dose study by 30%
and 50%, respectively, and were increased in
multiple-dose study by 23% and 30%, respectively.
CYP2C19*3, CYP2C19*17. The effects of *2 and *3
Foglia et al (1997) found that DCIT-to-CIT ratio
alleles (defective allele=def, i.e., CYP2C19*2 or *3)
decreased significantly when compared to that
show by slowing down citalopram metabolism. It was
suggested that subjects carrying *2 and *3 alleles
clearance for patients over 65 years of age was found
16.6 L/h whereas that for younger patients was found
concentration of desmethylcitalopram to citalopram
25.2 L/h, and as a result there was statistically
(MR) were determined to be 0.20±0.07, 0.15±0.05,
New Horizons in Science & Technology 1(2):27-32
0.07±0.03 in subjects with CYP2C19*1/*1 genotype,
THERAPEUTIC DRUG MONITORING
with CYP2C19*1/def , with CYP2C19 def/def,
respectively, (P<0.001). Citalopram oral clearances
The drug concentration in the blood depend
in subjects with CYP2C19def/def genotypes were
42.9% and 33.3% reduction compared with the
elimination of the drug. Drug metabolism, as well as
CYP2C19*1/*1 groups, CYP2C19*1/def groups,
other factors that affect the drug pharmacokinetic
parameter, varies from one patient to another, and the
Yu et al. (2003) reported that subjects with
interindividual variability of drug metabolism can
CYP2C19def/def genotypes had higher AUC0-∞
values, lower the oral clearance (CLoral) of
concentrations of psychoactive drugs from standard
citalopram than subjects with CYP2C19*1/*1, *1/def
doses (Dahl and Sjogvist, 2000; Hiemke, 2008a,b,c).
(P<0.01). Also, AUC0-∞ and Cmax of DCIT in
TDM could be a useful tool in the following
subjects with CYP2C19def/def genotypes were
significantly lower than the values of subjects with
CYP2C19*1/*1, *1/def genotypes (P<0.01). The
CYP2C19*1/*1, *1/def genotypes was almost three
non-response or occurrence of adverse effects at generally recommended doses
CYP2C19def/def genotypes (P<0.01).
suspicion of a particular metabolism in special
Concerning CYP2C19*17 polymorphism, its
results are controversial. The results of some studies showed
pharmacokinetic of the drugs used for the study (Sim
et al., 2006; Baldwin et al., 2008; Rudberg et al.,
TDM results can be used by the physicians
2008a; Wang et al., 2009), whereas those of other
to optimize dosage decisions in order to maximize
studies showed that polymorphism did not change
efficacy and prevent toxicity, especially when
pharmacokinetic of the drugs used for the study
individuals are nonresponsive to treatment or
(Ohlsson et al., 2008; Rudberg et al., 2008b). As a
vulnerable to adverse reactions with standard doses
result, it is reached that some of genetic
due to age, disease states or drug interactions. The
polymorphisms in genes that encode enzymes
results of some TDM studies are present in Table 2-5,
involved in metabolism of a drug can affect its
without mentioning genetic profile of subjects
pharmacokinetic, and thereby that *2 polymorphism
participating in these studies. These results are
limited due to the fact that plasma concentration may
not always guarantee usefulness and meaningfulness of the information.
Figure 1. The metabolism of citalopram (Unceta et al., 2011). New Horizons in Science & Technology 1(2):27-32 Table 2. Plasma concentrations of CIT and DCIT at different daily doses (Reis et al., 2002). Table 3. Plasma concentration of CIT and DCIT at different daily doses (Reis at al., 2003). Table 4. Median values of CIT and DCIT at different daily doses (Reis et al., 2009). Table 5. Plasma concentrations of CIT, DCIT, and DDCIT in 345 plasma samples of 258 depressive patients treated
with (10-360 mg/day) CIT (Le Bloc’h et al., 2003).
analysis. So that, the physician makes the patient's
pharmacokinetic of citalopram, which are intrinsic
treatment decision in more easier and more short
factors but the most important factor is person’s
time. This may also help physician in choosing the
genetic profile. The results by Le Bloc’h et al (2003)
right drug and the right starting dose for in time
and Reis et al (2002, 2003, 2009) were reported
according to daily doses used. * 2 polymorphism is
known to slow the metabolism of citalopram,
precisely. By determining the genetic profile of
subjects involved the studies, CIT plasma levels may
Baldwin, R.M., Ohlsson, S., Pedersen, R.S., Mwinyi,
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Bertilsson, L. 2008. Increased omeprazole
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a pharmacokinetic study in healthy volunteers.
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should be supported with data obtained by genotype
New Horizons in Science & Technology 1(2):27-32
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