Abstract
Escitalopram is the (S)-enantiomer of the racemic selective serotonin reuptake inhibitor antidepressant citalopram. Clinical studies have shown that escitalopram is effective and well tolerated in the treatment of depression and anxiety disorders. Following oral administration, escitalopram is rapidly absorbed and reaches maximum plasma concentrations in approximately 3–4 hours after either single-or multiple-dose administration. The absorption of escitalopram is not affected by food. The elimination half-life of escitalopram is about 27–33 hours and is consistent with once-daily administration. Steady-state concentrations are achieved within 7–10 days of administration. Escitalopram has low protein binding (56%) and is not likely to cause interactions with highly protein-bound drugs. It is widely distributed throughout tissues, with an apparent volume of distribution during the terminal phase after oral administration (Vz/F) of about 1100L. Unmetabolised escitalopram is the major compound in plasma. S-demethylcitalopram (S-DCT), the principal metabolite, is present at approximately one-third the level of escitalopram; however, S-DCT is a weak inhibitor of serotonin reuptake and does not contribute appreciably to the therapeutic activity of escitalopram. The didemethyl metabolite of escitalopram (S-DDCT) is typically present at or below quantifiable concentrations. Escitalopram and S-DCT exhibit linear and dose-proportional pharmacokinetics following single or multiple doses in the 10–30 mg/day dose range. Adolescents, elderly individuals and patients with hepatic impairment do not have clinically relevant differences in pharmacokinetics compared with healthy young adults, implying that adjustment of the dosage is not necessary in these patient groups. Escitalopram is metabolised by the cytochrome P450 (CYP) isoenzymes CYP2C19, CYP2D6 and CYP3A4. However, ritonavir, a potent inhibitor of CYP3A4, does not affect the pharmacokinetics of escitalopram. Coadministration of escitalopram 20mg following steady-state administration of cimetidine or omeprazole led to a 72% and 51% increase, respectively, in escitalopram exposure compared with administration alone. These changes were not considered clinically relevant. In vitro studies have shown that escitalopram has negligible inhibitory effects on CYP isoenzymes and P-glycoprotein, suggesting that escitalopram is unlikely to cause clinically significant drug-drug interactions. The favourable pharmacokinetic profile of escitalopram suggests clinical utility in a broad range of patients.
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References
Burke WJ. Escitalopram. Expert Opin Investig Drugs 2002; 11(10): 1477–86
Hyttel J, Bogeso KP, Perregaard J, et al. The pharmacological effect of citalopram resides in the (S)-(+)-enantiomer. J Neural Transm Gen Sect 1992; 88(2): 157–60
Sanchez C, Bergqvist PB, Brennum LT, et al. Escitalopram, the S-(+)-enantiomer of citalopram, is a selective serotonin reuptake inhibitor with potent effects in animal models predictive of antidepressant and anxiolytic activities. Psychopharmacology (Berl) 2003; 167(4): 353–62
Sanchez C, Bogeso KP, Ebert B, et al. Escitalopram versus citalopram: the surprising role of the R-enantiomer. Psychopharmacology (Berl) 2004; 174(2): 163–76
Owens MJ, Knight DL, Nemeroff CB. Second-generation SS-RIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine. Biol Psychiatry 2001; 50(5): 345–50
von Moltke LL, Greenblatt DJ, Giancarlo GM, et al. Escitalopram (S-citalopram) and its metabolites in vitro: cytochromes mediating biotransformation, inhibitory effects, and comparison to R-citalopram. Drug Metab Dispos 2001; 29(8): 1102–9
Stahl SM, Gergel I, Li D. Escitalopram in the treatment of panic disorder: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2003; 64(11): 1322–7
Burke WJ, Gergel I, Bose A. Fixed-dose trial of the single isomer SSRI escitalopram in depressed outpatients. J Clin Psychiatry 2002; 63(4): 331–6
Wade A, Michael Lemming O, Bang Hedegaard K. Escitalopram 10 mg/day is effective and well tolerated in a placebo-controlled study in depression in primary care. Int Clin Psychopharmacol 2002; 17(3): 95–102
Rapaport MH, Bose A, Zheng H. Escitalopram continuation treatment prevents relapse of depressive episodes. J Clin Psychiatry 2004; 65(1): 44–9
Waugh J, Goa KL. Escitalopram: a review of its use in the management of major depressive and anxiety disorders. CNS Drugs 2003; 17(5): 343–62
Davidson JR, Bose A, Korotzer A, et al. Escitalopram in the treatment of generalized anxiety disorder: double-blind, placebo controlled, flexible-dose study. Depress Anxiety 2004; 19(4): 234–40
Montgomery SA, Loft H, Sanchez C, et al. Escitalopram (S-enantiomer of citalopram): clinical efficacy and onset of action predicted from a rat model. Pharmacol Toxicol 2001; 88(5): 282–6
Gorman JM, Korotzer A, Su G. Efficacy comparison of escitalopram and citalopram in the treatment of major depressive disorder: pooled analysis of placebo-controlled trials. CNS Spectrums 2002; 7 (4 Suppl.1): 40–4
Drewes P, Thijssen I, Mengel H, et al. A single-dose cross-over pharmacokinetic study comparing racemic citalopram (40 mg) with the S-enantiomer of citalopram (escitalopram, 20 mg) in healthy male subjects [abstract]. National Institute of Mental Health/41 st Annual New Clinical Drug Evaluation Unit Meeting, 2001 May 28–31; Phoenix (AZ) [online]. Available from URL: http://www.nimh.nih.gov/ncdeu/abstracts2001/ncdeu2045.cfm [Accessed 2006 Nov 8]
Sogaard B, Mengel H, Rao N, et al. The pharmacokinetics of escitalopram after oral and intravenous administration of single and multiple doses to healthy subjects. J Clin Pharmacol 2005; 45(12): 1400–6
Joffe P, Larsen FS, Pedersen V, et al. Single-dose pharmacokinetics of citalopram in patients with moderate renal insufficiency or hepatic cirrhosis compared with healthy subjects. Eur J Clin Pharmacol 1998; 54(3): 237–42
Sidhu J, Priskorn M, Poulsen M, et al. Steady-state pharmacokinetics of the enantiomers of citalopram and its metabolites in humans. Chirality 1997; 9(7): 686–92
Rochat B, Amey M, Baumann P. Analysis of enantiomers of citalopram and its demethylated metabolites in plasma of depressive patients using chiral reverse-phase liquid chromatography. Ther Drug Monit 1995; 17(3): 273–9
Forest Pharmaceuticals, Inc. Prescribing information for Lexapro (escitalopram oxalate). St Louis (MO): Forest Pharmaceuticals, Inc., 2006 [online]. Available from URL: http://www.lexapro.com/pdf/lexapro_pi.pdf [Accessed 2007 Feb 22]
Gutierrez M, Mengel H. Pharmacokinetics of escitalopram [abstract]. National Institute of Mental Health/42nd Annual New Clinical Drug Evaluation Unit Meeting, June 10–13, 2002; Boca Raton, FL [online]. Available from URL: http://www.nimh.nih.gov/ncdeu/abstracts2002/ncdeu2002.cfm [Accessed 2006 Nov 8]
Uhr M, Grauer MT. abcblab P-glycoprotein is involved in the uptake of citalopram and trimipramine into the brain of mice. J Psychiatr Res 2003; 37(3): 179–85
Uhr M, Grauer MT, Holsboer F. Differential enhancement of antidepressant penetration into the brain in mice with abcblab (mdrlab) P-glycoprotein gene disruption. Biol Psychiatry 2003; 54(8): 840–6
Uhr M, Steckler T, Yassouridis A, et al. Penetration of amitriptyline, but not of fluoxetine, into brain is enhanced in mice with blood-brain barrier deficiency due to mdrla P-glycoprotein gene disruption. Neuropsychopharmacology 2000; 22(4): 380–7
Rochat B, Baumann P, Audus KL. Transport mechanisms for the antidepressant citalopram in brain microvessel endothelium. Brain Res 1999; 831(1–2): 229–36
Oyehaug E, Ostensen ET, Salvesen B. High-performance liquid chromatographic determination of citalopram and four of its metabolites in plasma and urine samples from psychiatric patients. J Chromatogr 1984; 308: 199–208
Rochat B, Amey M, Van Gelderen H, et al. Determination of the enantiomers of citalopram, its demethylated and propionic acid metabolites in human plasma by chiral HPLC. Chirality 1995; 7(6): 389–95
Desta Z, Zhao X, Shin JG, et al. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet 2002; 41(12): 913–58
Herrlin K, Yasui-Furukori N, Tybring G, et al. Metabolism of citalopram enantiomers in CYP2C19/CYP2D6 phenotyped panels of healthy Swedes. Br J Clin Pharmacol 2003; 56(4): 415–21
Rochat B, Kosel M, Boss G, et al. Stereoselective biotransformation of the selective serotonin reuptake inhibitor citalopram and its demethylated metabolites by monoamine oxidases in human liver. Biochem Pharmacol 1998; 56(1): 15–23
Kosel M, Gnerre C, Voirol P, et al. In vitro biotransformation of the selective serotonin reuptake inhibitor citalopram, its enantiomers and demethylated metabolites by monoamine oxidase in rat and human brain preparations. Mol Psychiatry 2002; 7(2): 181–8
Kragh-Sorensen P, Overo KF, Petersen OL, et al. The kinetics of citalopram: single and multiple dose studies in man. Acta Pharmacol Toxicol (Copenh) 1981; 48(1): 53–60
Dalgaard L, Larsen C. Metabolism and excretion of citalopram in man: identification of O-acyl- and N-glucuronides. Xenobiotica 1999; 29(10): 1033–41
Periclou A, Rao N, Sherman T, et al. Single-dose pharmacokinetic study of escitalopram in adolescents and adults [abstract]. Pharmacotherapy 2003; 23(10): 1361–2
Areberg J, Christophersen JS, Poulsen MN, et al. The pharmacokinetics of escitalopram in patients with hepatic impairment. AAPS J 2006; 8(1): E14–9
Greenblatt DJ, von Moltke LL, Harmatz JS, et al. Drug interactions with newer antidepressants: role of human cytochromes P450. J Clin Psychiatry 1998; 59 Suppl. 15: 19–27
Ketter TA, Flockhart DA, Post RM, et al. The emerging role of cytochrome P450 3A in psychopharmacology. J Clin Psychopharmacol 1995; 15(6): 387–98
Harvey AT, Preskorn SH. Cytochrome P450 enzymes: interpretation of their interactions with selective serotonin reuptake inhibitors. Part II. J Clin Psychopharmacol 1996; 16(5): 345–55
Hemeryck A, De Vriendt C, Belpaire FM. Inhibition of CYP2C9 by selective serotonin reuptake inhibitors: in vitro studies with tolbutamide and (S)-warfarin using human liver microsomes. Eur J Clin Pharmacol 1999; 54(12): 947–51
Lane RM. Pharmacokinetic drug interaction potential of selective serotonin reuptake inhibitors. Int Clin Psychopharmacol 1996; 11 Suppl. 5: 31–61
Hemeryck A, Belpaire FM. Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug-drug interactions: an update. Curr Drug Metab 2002; 3(1): 13–37
Brosen K, Skjelbo E, Rasmussen BB, et al. Fluvoxamine is a potent inhibitor of cytochrome P4501A2. Biochem Pharmacol 1993; 45(6): 1211–4
Rasmussen BB, Nielsen TL, Brosen K. Fluvoxamine inhibits the CYP2C19-catalysed metabolism of proguanil in vitro. Eur J Clin Pharmacol 1998; 54(9–10): 735–40
Gutierrez MM, Rosenberg J, Abramowitz W. An evaluation of the potential for pharmacokinetic interaction between escitalopram and the cytochrome P450 3A4 inhibitor ritonavir. Clin Ther 2003; 25(4): 1200–10
Mailing D, Poulsen MN, Sogaard B. The effect of cimetidine or omeprazole on the pharmacokinetics of escitalopram in healthy subjects. Br J Clin Pharmacol 2005; 60(3): 287–90
Gram LF, Hansen MG, Sindrup SH, et al. Citalopram: interaction studies with levomepromazine, imipramine, and lithium. Ther Drug Monit 1993; 15(1): 18–24
Baettig D, Bondolfi G, Montaldi S, et al. Tricyclic antidepressant plasma levels after augmentation with citalopram: a case study. Eur J Clin Pharmacol 1993; 44(4): 403–5
Larsen F, Priskorn M, Overo KF. Lack of citalopram effect on oral digoxin pharmacokinetics. J Clin Pharmacol 2001; 41(3): 340–6
Baumann P, Nil R, Souche A, et al. A double-blind, placebo-controlled study of citalopram with and without lithium in the treatment of therapy-resistant depressive patients: a clinical, pharmacokinetic, and pharmacogenetic investigation. J Clin Psychopharmacol 1996; 16(4): 307–14
Nolting A, Abramowitz W. Lack of interaction between citalopram and the CYP3A4 substrate triazolam. Pharmacotherapy 2000; 20(7): 750–5
Priskorn M, Sidhu JS, Larsen F, et al. Investigation of multiple dose citalopram on the pharmacokinetics and pharmacodynamics of racemic warfarin. Br J Clin Pharmacol 1997; 44(2): 199–202
Möller SE, Larsen F, Pitsiu M, et al. Effect of citalopram on plasma levels of oral theophylline. Clin Ther 2000; 22(12): 1494–501
Steinacher L, Vandel P, Zullino DF, et al. Carbamazepine augmentation in depressive patients non-responding to citalopram: a pharmacokinetic and clinical pilot study. Eur Neuropsychopharmacol 2002; 12(3): 255–60
Möller SE, Larsen F, Khant AZ, et al. Lack of effect of citalopram on the steady-state pharmacokinetics of carbamazepine in healthy male subjects. J Clin Psychopharmacol 2001; 21(5): 493–9
Bondolfi G, Chautems C, Rochat B, et al. Non-response to citalopram in depressive patients: pharmacokinetic and clinical consequences of a fluvoxamine augmentation. Psychopharmacology (Berl) 1996; 128(4): 421–5
Bondolfi G, Lissner C, Kosel M, et al. Fluoxetine augmentation in citalopram non-responders: pharmacokinetic and clinical consequences. Int J Neuropsychopharmacol 2000; 3(1): 55–60
Weiss J, Dormann SM, Martin-Facklam M, et al. Inhibition of P-glycoprotein by newer antidepressants. J Pharmacol Exp Ther 2003; 305(1): 197–204
Acknowledgements
This work was supported by Forest Laboratories, Inc., New York, NY, USA.
The author would like to thank Jennifer Kaiser, PhD, Denise Bonen, PhD, Chetan Gandhi, PhD, and Adam Ruth, PhD, for their contributions in the development of this manuscript.
The author was an employee of Forest Laboratories during the preparation of this manuscript.
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Rao, N. The Clinical Pharmacokinetics of Escitalopram. Clin Pharmacokinet 46, 281–290 (2007). https://doi.org/10.2165/00003088-200746040-00002
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DOI: https://doi.org/10.2165/00003088-200746040-00002