Autonomic Control in Patients Experiencing Atrial Fibrillation After Cardiac Surgery ROBERT BAUERNSCHMITT, M.D.,* HAGEN MALBERG, PH.D.,† NIELS WESSEL, PH.D.,‡ GERNOT BROCKMANN, M.D.,* STEPHEN M. WILDHIRT, M.D.,* BURKHARD KOPP, PH.D.,* J ¨ URGEN KURTHS, PH.D.,‡ GEORG BRETTHAUER, PH.D.,† and R ¨From the *Department of Cardiovascular Surgery, German Heart Center, Munich, Germany, †Ins
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Microsoft word - 02-galley_proof__nhs&t_12-153_zuhal_uckun__2_.docx_without_track_changes.docxNew 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
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
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 Metabolism
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 PHARMACOKINETIC
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 Elimination
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
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- (http://www.cypalleles.ki.se/cyp2c19.htm life were increased in a single –dose study by 30% http://www.cypalleles.ki.se/cyp3a4.htm). 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, REFERENCES
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SARATOV / ENGELS – BEMIDJI AIHA PARTNERSHIP ASSESSMENT OF HIV/AIDS Care - Adults HIV/AIDS Care and Outcomes Chart Audit for Quality Assurance and Quality Improvement Contents Preface and Quick-Start Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .